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Olaparib, a potent PARP inhibitor, has been shown to have great anti-tumor effects in some tumor types. Although biliary tract cancer (BTC) is a good candidate for DNA damage response (DDR)-targeted agents, targeted DDR inhibitors, including olaparib, are currently rarely evaluated in BTC. In our project, a total of ten BTC cell lines were used to assess the efficacy of olaparib. Olaparib alone showed moderate anti-proliferative effects in BTC cells and increased p-ATR and PD-L1 expression levels. In combination with an ATR inhibitor (AZD6738, ceralasertib) showed synergistic anti-proliferative effects and increased DNA strand breaks in vitro. PD-L1 induced by olaparib was also downregulated by ceralasertib through p-STAT-3 and YAP reduction with or without human primary peripheral blood mononuclear cells. In SNU478-xenograft models, the combination treatment significantly suppressed tumor growth. PD-L1 and YAP were strongly downregulated, similar to in vitro conditions, and expression of CXCR2 and CXCR4 was further reduced. In the current ongoing clinical trial (NCT04298021), BTC patients treated with olaparib and ceralasertib combination have shown tumor response. In conclusion, co-targeting of PARP and ATR might be a potential therapeutic approach for patients with BTC.

To date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer. However, there is still a huge unmet medical need for patients with trastuzumab resistance. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). Here, we found higher PD-L1 expression in trastuzumab-resistant (HR) HER2-positive cancer cells than in parental cells, and blocking PD-L1 reversed the resistance to trastuzumab in HR cells. Trastuzumab upregulated PD-L1 expression via NF-κB activation in both parental and HR cells, however, led to DNA damage only in parental cells. The WEE1 inhibitor adavosertib, which downregulates PD-L1 expression, enhanced trastuzumab efficacy by blocking BRCA1-CMTM6-PD-L1 signals and the HER2-CDCP-1-SRC axis. Additionally, the levels of galectin-9, CD163, FoxP3, and CTLA-4 were diminished by blocking WEE1 in the presence of human PBMCs in vitro. Taken together, the strategy of co-targeting HER2 and WEE1 could overcome resistance to trastuzumab in HER2-positive cancers, supporting further clinical development in HER2-positive cancer patients.

BACKGROUND This study aimed to evaluate the association between soluble TGF-β (sTGF-β) and soluble PD-L1 (sPDL1), the dynamics of sTGF-β during treatment and its prognostic role in biliary tract cancer (BTC). METHODS The study population consisted of 90 BTC patients with first-line chemotherapy (cohort 1) and 35 BTC patients with second- or third-line chemotherapy (cohort 2). Plasma sTGF-β and sPDL1 levels were measured using an enzyme-linked immunosorbent assay. RESULTS In both groups, sTGF-β was positive correlated with sPDL1 for baseline and change values after treatment. sTGF-β was elevated at disease progression compared to baseline in cohort 1 (P

PurposeCurrently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC.Materials and MethodsIn this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models.ResultsAZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy.ConclusionTaken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

Background: PARP inhibitors have shown antitumor activities against solid tumors with HRD (homologous recombination deficiency). The definition of HRD and other potential biomarkers besides HRD should be further evaluated for PARP inhibitors. JPI-547 is a novel PARP inhibitor, simultaneously targeting tankyrase1/2, other members of the PARP family, that are involved in the Wnt/β-catenin pathway. Method: Antiproliferative effect of JPI-547 and a variety of PARP inhibitors (olaparib, veliparib, talazoparib, niraparib, and rucaparib) were determined by MTT assay or clonogenic assay in 9 human pancreatic ductal adenocarcinoma (PDAC) cell lines (Capan-1, HPAF-II, Capan-2, AsPC-1, SNU-410, SNU-213, SNU-324, MIA-PaCa2, and PANC-1). Transcriptome data and gene dependency score of the cell lines were obtained from the CCLE database and DepMap respectively. DNA damage was monitored by immunofluorescent imaging of γ-H2AX and DR-GFP assay determined the homologous recombination repair (HRR) efficiency. A xenograft tumor model was established to substantiate the in vivo antitumor effect of JPI-547. Results: JPI-547 more potently blocks Poly(ADP-ribosyl)ation than olaparib, and induces a strong antiproliferative effect on Capan-1, a cell line with BRCA2 del. JPI-547 leads to cell cycle arrest and induces enhanced apoptotic cell death than olaparib. JPI-547 inhibits tumor growth of Capan-1 in vivo, suggesting the potent antitumor activity of JPI-547 against PDAC with HRD. Cell lines harboring RNF43 LOF mutations (HPAF-II, AsPC-1, and Capan-2), intrinsically addicted to Wnt/β-catenin pathway, are more sensitive to JPI-547 than cells with RNF43 wild types. Interestingly, RNF43 mutations could not distinguish the sensitivity of other PARP inhibitors except JPI-547. CTNNB1 gene dependency score and β-catenin levels positively correlate with cellular sensitivity to JPI-547. JPI-547-induced DNA damage was alleviated in HR-proficient PDAC cells. DR-GFP assays confirm that JPI-547 does not directly alter the HRR efficiency of Wnt-addicted PDAC cells. Collectively, these data indicate that the vulnerabilities of Wnt-addicted PDAC cells to JPI-547 were irrelevant to HRD mimicking. Rather, JPI-547 stabilizes AXIN-2 in Wnt-addicted PDAC cells and downregulates the active form of β-catenin level in the nucleus, thereby disrupting the transcription of its target genes. Knockdown of β-catenin neutralized the antiproliferative effect of JPI-547, suggesting that inhibition of the β-catenin pathway is an important mode of action by JPI-547 in Wnt-addicted PDAC cells. Conclusion: JPI-547 shows promising, preclinical antitumor effects against PDAC cells with HRD or Wnt-addiction, providing a rationale for further biomarker-driven clinical development of JPI-547 for the treatment of patients with PDAC. Citation Format: Kyoung-Seok Oh, Ah-Rong Nam, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Su In Lee, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Banyoon Cheon, Hyunju Cha, John Kim, Do-Youn Oh. JPI-547, a dual inhibitor of PARP/Tankyrase, shows promising antitumor activity against pancreatic cancers with homologous recombination repair deficiency or Wnt-addiction. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4496.

Background: HER2 (Human epithelial growth factor receptor 2)-targeting therapies have been approved for patients with HER2-positive breast and gastric cancer and use have been attempted in various solid tumor types, including biliary tract cancer. However, resistance mechanism remains as a major challenge of HER2-targeting therapies. YAP (Yes-associated protein) is a major downstream effector of Hippo pathway, and it plays an essential role in cancer cell proliferation, survival and differentiation. Moreover, YAP is emerging as a key player of resistance mechanism of cytotoxic and targeted drugs. Yap is also an important immunosuppressive molecule as it works as a negative regulator of T cell tumor infiltration. In this study, we intend to elucidate the role of YAP in mechanism of trastuzumab resistance and T cell immune response in HER2-positive cancer cells. Methods: We established four trastuzumab-resistant (HR) cell lines (N87HR, SNU216HR, SNU2670HR and SNU2773HR) from HER2-postive gastric and biliary tract cancer cell lines. To inhibit the function of YAP, siRNA and Verteporfin (YAP-TEAD inhibitor) were used. MTT assay, cell cycle analysis, western blot and migration assay were performed to analyze the antitumor effects through YAP downregulation. In order to evaluate immune-modulation by YAP, human PBMC co-culture was used and immune markers were analyzed by RT-PCR and flow cytometry. Mouse xenograft models were established using SNU2773 and SNU2773HR cells. Results: We confirmed that the expressions of pYAP and YAP were elevated in HR cells (SNU216HR, SNU2670HR and SNU2773HR) compared to parental cells. Reducing the expressed YAP in HR cells inhibited tumor cell growth and migration and induced apoptosis. Immune suppression markers such as PD-L1, CD155, and galectin-9 were effectively decreased, while CD80, a stimulation marker, was increased by verteporfin treatment. Also, when YAP was decreased, CCL5 and CXCL10, well known CD8+ T cell recruitment cytokines, were increased. In HR cells treated with siYAP and verteporfin, there was a trend of increasing CD4+ and CD8+ T cells when co-culture with PBMC. In vivo experiment data showed greater tumor growth inhibition effects with SNU2773HR than SNU2773 xenograft models when treated with verteporfin. Conclusion: The expression of YAP is elevated in trastuzumab-resistant (HR) cells and inhibition of YAP shows anti-tumor effects and activation of T cell responses. Collectively, our data suggests that the inhibition of YAP is one of many promising strategies to overcome trastuzumab resistance and T cell regulatory mechanisms in HER2-positive cancers. Citation Format: Ah Rong Nam, Jeesun Yoon, Kyoung-Seok Oh, Jae-Min Kim, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Su In Lee, Tae-Yong Kim, Do-Youn Oh. Targeting of YAP overcomes trastuzumab-resistance and promotes immune responses in HER2-positive cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3872.

404 Background: DNA damage response (DDR) gene alterations are observed in 27% of gastric cancer (GC), therefore, targeting DDR might be an interesting strategy in GC. Olaparib plus paclitaxel showed numerically improved overall survival (OS) compared to paclitaxel in 2L GC patients (pts), even though it did not meet the endpoint. (Lancet Oncol 2017). Besides DNA damage repair, olaparib induces immune modulation. The role of immune checkpoint inhibitor (ICI) is established in 1L and 3L+ GC. The combination of cytotoxic chemotherapy, DDR acting agent and ICI might have synergistic effects in GC, which has not been tested in clinical studies. Here, we report biomarker-oriented phase II study of paclitaxel/olaparib/durvalumab combination in 2L GC. (NCT03579784). Methods: Advanced GC pts who have failed to 1L chemotherapy were enrolled. During 1st cycle, paclitaxel (80 mg/m2, D1, 8, 15 Q 4wk) and olaparib (150mg bid, D1-28) was administered. From 2nd cycle, durvalumab (1500 mg, D1 Q 4wk) was added on them. Tumor biopsy (pretreatment, after 1st cycle, at disease progression) and blood collection (every cycle) was mandatory. Primary endpoint was the disease control rate (DCR). Secondary endpoints included ORR, DoR, PFS, OS and safety. For biomarker study, multiplex IHC, NGS, ctDNA, and cytokines and angiogenic factors analysis were performed. Efficacy analysis set (ES) and safety analysis set (SS) were defined as pts who underwent at least one tumor assessment and all pts who received cycle1 day1 or more, respectively. Results: Fifty pts were enrolled (6 screening fail or withdrawal of consent, 44 in SS, 38 in ES) HER2+ GC were 13.2%. Among 38 in ES, DCR and ORR were 84.1% (95% CI, 72.5-95.7) and 39.5% (95% CI, 24.0-55.0) (1 CR, 14 PR and 17 SD). PFS, DoR and OS were 6.7 (95% CI, 4.5-10.3), 6.5 (95% CI, 5.1-10.7) and 11.4 (95% CI, 9.2-13.2) months. Homologous recombination repair (HRR) genetic alterations (9.6 vs. 5.9 in PFS, p=0.037), high CD8/CD3 ratio (8.8 vs. 3.7 in PFS, p=0.008), high PD-L1 (CPS≥10) (9.6 vs 5.1 in PFS, p=0.031), low ATM IHC (13.3 vs. 9.8 in OS, p=0.066), and low serum IL-6 (12.9 vs. 8.3 in OS, p=0.001) were associated with prolonged PFS or OS. In SS, most adverse events (AEs) were mild, and Gr 3/4 leukopenia and anemia were observed in 52.2% and 31.8%. There were no treatment related AEs resulted in study discontinuation. Conclusions: Paclitaxel/olaparib/durvalumab is a promising combination in 2L GC, and is worth to be further explored, especially in biomarker-enriched patients with HRR, specific T-cells subsets, high PD-L1, low ATM and IL-6. Clinical trial information: NCT03579784 .

Immunotherapies have shown clinical activity in patients with advanced biliary tract cancer, for which outcomes remain poor despite standard of care treatment with gemcitabine and cisplatin. We aimed to evaluate gemcitabine and cisplatin plus durvalumab with or without tremelimumab as first-line treatment in patients with advanced biliary tract cancer.This open-label, single-centre, phase 2 study was conducted at Seoul National University Hospital. Eligible patients were treatment-naïve adults aged 18 years or older with histologically proven unresectable or recurrent biliary tract cancer, at least one measurable lesion based on the Response Evaluation Criteria in Solid Tumors (version 1.1), an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 12 weeks or longer, and adequate healthy organ and bone marrow function. Initially, all patients received one 3-week cycle of gemcitabine (1000 mg/mBetween March 2, 2017, and Feb 13, 2020, 128 patients were enrolled (32 in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 49 in the chemotherapy plus durvalumab group, and 47 in the chemotherapy plus durvalumab and tremelimumab group). Four patients (two in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group and two in the chemotherapy plus durvalumab group) were excluded and 124 were evaluable for tumour response. The median duration of follow-up was 48·2 months (IQR 41·5-49·4) for the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 26·6 months (19·0-27·9) for the chemotherapy plus durvalumab group, and 24·2 months (20·7-31·7) for the chemotherapy plus durvalumab and tremelimumab group. 82 (66%) of 124 patients achieved an objective response (15 [50%] of 30 in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 34 [72%] of 47 in the chemotherapy plus durvalumab group, and 33 [70%] of 47 in the chemotherapy plus durvalumab and tremelimumab group). The most common grade 3 and 4 adverse events were decreased neutrophil count (67 [53%] of 126), anaemia (50 [40%]), and decreased platelet count (24 [19%]), with no unexpected safety events. No adverse events leading to discontinuation or death occurred.Gemcitabine and cisplatin plus immunotherapy showed promising efficacy and acceptable safety in patients with biliary tract cancer. Gemcitabine and cisplatin plus durvalumab are being evaluated in the phase 3, TOPAZ-1 study (NCT03875235) as first-line treatment in patients with advanced biliary tract cancer.AstraZeneca; National Research Foundation of Korea (Grant No. 2021R1A2C2007430).

Despite its clinical efficacy in HER2-positive cancers, resistance to trastuzumab inevitably occurs. The DNA damage response (DDR) pathway is essential for maintaining genomic stability and cell survival. However, the role of the DDR pathway in HER2-positive tumors and trastuzumab resistance remains elusive. In this study, we verified that increased PARP1 expression in trastuzumab-resistant (TR) cells, owing to its augmented stability by escape from proteasomal degradation, confers tolerability to trastuzumab-induced DNA damage. Interruption of PARP1 in TR cells restrains its cellular growth, while simultaneously activating ATM to retain its genome stability. Dual inhibition of PARP and ATM induces synthetic lethality in TR cells by favoring the toxic NHEJ pathway instead of the HRR pathway. Our results highlight the potential of clinical development of DDR-targeting strategies for trastuzumab-resistant HER2-positive cancer patients.

Purpose Up to 20% of patients with biliary tract cancer (BTC) have alterations in DNA damage response (DDR) genes, including homologous recombination (HR) genes. Therefore, the DDR pathway could be a promising target for new drug development in BTC. We aim to investigate the anti-tumor effects using poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors in BTC.Materials and Methods We used 10 BTC cell lines to evaluate an anti-tumor effect of olaparib (a PARP inhibitor) and AZD1775 (a WEE1 inhibitor) in in vitro. Additionally, we established SNU869 xenograft model for in vivo experiments.Results In this study, we observed a modest anti-proliferative effect of olaparib. DNA double-strand break (DSB) and apoptosis were increased by olaparib in BTC cells. However, olaparib-induced DNA DSB was repaired through the HR pathway, and G2 arrest was induced to secure the time for repair. As AZD1775 typically regulates the G2/M checkpoint, we combined olaparib with AZD1775 to abrogate G2 arrest. We observed that AZD1775 downregulated p-CDK1, a G2/M cell cycle checkpoint protein, and induced early mitotic entry. AZD1775 also decreased CtIP and RAD51 expression and disrupted HR repair. In xenograft model, olaparib plus AZD1775 treatment reduced tumor growth more potently than did monotherapy with either drug.Conclusion This is the first study to suggest that olaparib combined with AZD1775 can induce synergistic anti-tumor effects against BTC. Combination therapy that blocks dual PARP and WEE1 has the potential to be further clinically developed for BTC patients.

To date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer. However, there is still a huge unmet medical need for patients with trastuzumab resistance.In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773).Here, we found higher PD-L1 expression in trastuzumab-resistant (HR) HER2-positive cancer cells than in parental cells, and blocking PD-L1 reversed the resistance to trastuzumab in HR cells. Trastuzumab upregulated PD-L1 expression via NF-κB activation in both parental and HR cells, however, led to DNA damage only in parental cells. The WEE1 inhibitor adavosertib, which downregulates PD-L1 expression, enhanced trastuzumab efficacy by blocking BRCA1-CMTM6-PD-L1 signals and the HER2-CDCP-1-SRC axis. Additionally, the levels of galectin-9, CD163, FoxP3, and CTLA-4 were diminished by blocking WEE1 in the presence of human PBMCs in vitro.Taken together, the strategy of co-targeting HER2 and WEE1 could overcome resistance to trastuzumab in HER2-positive cancers, supporting further clinical development in HER2-positive cancer patients.

Purpose The soluble form programmed death-ligand 1 (sPDL1) has immunosuppressive properties and is being studied as a candidate biomarker for immuno-oncology drug development. We measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in advanced gastric cancer (GC).Materials and Methods We prospectively enrolled 68 GC patients who were candidates for palliative standard first-line chemotherapy, and serially collected blood at baseline and after one cycle of chemotherapy, at the best response and after disease progression. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS), progressionfree survival (PFS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were obtained. The cut-off value of sPDL1 levels for survival analysis was found using C-statistics.Results The median baseline sPDL1 was 0.8 ng/mL (range, 0.06 to 6.06 ng/mL). The median OS and PFS were 14.9 months and 8.0 months, respectively. sPDL1 and NLR showed a weak positive correlation (Spearman’s rho=0.301, p=0.013). Patients with low levels of sPDL1 at diagnosis (< 1.92 ng/mL) showed a better OS and PFS than patients with a high sPDL1. The baseline sPDL1 before treatment was higher in the progressive disease group than in the stable disease and partial response groups. Patients whose sPDL1 increased after the first cycle of chemotherapy showed worse PFS and OS. Following disease progression, sPDL1 increased compared with the baseline.Conclusion sPDL1 at prechemotherapy confers a prognostic value for PFS and OS in GC patients under palliative first-line chemotherapy. Dynamics of sPDL1 during chemotherapy correlates with disease progression.

Background: Human epithelial growth factor receptor 2 (HER2) is a well-established therapeutic target in HER2-positive breast and gastric cancer. Recently, novel HER2-targeting agents are being developed after trastuzumab, and HER2-targeted therapies have been attempted in across solid tumor types, including biliary tract cancer. In these aspects, it is essential to understand and elucidate the resistant mechanism of the HER2-targeting strategies. Yes-associated protein (YAP), a transcription factor of the Hippo pathway, function as proto-oncoproteins by inducing target genes involved in cancer cell survival and proliferation (Zhao B, et al. Genes Develop 2008). Also, YAP is emerging as a resistance mechanism of cytotoxic and targeted drugs. In this study, we explore the role of YAP in overcoming resistance to trastuzumab in HER2-positive cancer cells. Methods: Four trastuzumab-resistant (HR) cell lines were established using HER2-postive gastric and biliary tract cancer cell lines (N87, SNU216, SNU2670, and SNU2773) (Jin MH, et al. Mol Cancer Ther. 2017). YAP siRNA and Verteporfin (YAP-TEAD inhibitor) were used to downregulate YAP. MTT assay, cell cycle analysis, western blot and migration assay were performed to analyze the antitumor effects through YAP downregulation. In order to elucidate tumor cell immune-modulation by YAP, human PBMC co-culture was used and immune markers, such as programmed death-ligand 1 (PD-L1), were analyzed in HR cell lines. Results: Increase of receptor tyrosine kinase-like orphan receptor 1/2 (ROR1/2) expression was observed in the HR cells. Relatively high expression of pYAP, YAP, and transcriptional co-activator with PDZ-binding motif (TAZ) were observed in the HR cells (SNU216HR, SNU2670HR and SNU2773HR) compared to parental cells. Reducing overexpressed YAP in HR cells resulted in tumor cell growth inhibition. In cell cycle analysis, the increase of subG1 phase through YAP downregulation was observed, and cyclinD, B, A and BCL-XL were effectively decreased. Migration was also inhibited by the decrease in YAP expression. By verteporfin treatment, changes in immune markers including increase of CD80 and decrease of PD-L1 was found. In addition, p-STAT3 and IL6, Which regulate PD-L1, were also decreased through the reduction of YAP. In HR cells treated with siYAP, there was a tendency to increase CD8+ T cells upon PBMC co-culture. Conclusion: YAP is upregulated in trastuzumab-resistant (HR) cells and upregulated YAP induce PD-L1 expression. Inhibition of YAP shows anti-tumor effects and modulates immune status. Collectively, our results suggest that inhibition of YAP is one of promising strategies to overcome trastuzumab resistance in HER2-positive cancers. Citation Format: Ah Rong Nam, Jeesun Yoon, Kyoung-Seok Oh, Jae-Min Kim, Ju-Hee Bang, Tae-Yong Kim, Do-Youn Oh. Targeting the hippo transducer YAP overcomes trastuzumab-resistance in HER2-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5334.

4117 Background: In the phase 2 (NCT03046862), gemcitabine/cisplatin (GemCis) and durvalumab (D) ± tremelimumab (T) in chemotherapy-naïve advanced biliary tract cancer (BTC) showed a high objective response rate and durable clinical benefit. Based on this study, phase 3 trial (TOPAZ-1, NCT03875235) has been conducted and the positive result for adding D to GemCis has been reported. Health-related quality of life (HRQoL) for adding immunotherapy to cytotoxic chemotherapy in BTC has not been reported yet. We present HRQoL results from the phase 2 study. Methods: In this study, treatment-naïve patients with unresectable or recurrent BTC were enrolled into three cohorts. Patients received one cycle of GemCis followed by GemCis plus D and T (cohort 1) or, starting with the first cycle, received GemCis plus D (cohort 2) or GemCis plus D and T (cohort 3). The EORTC Quality of Life Questionnaire (QLQ)-C30 and BIL21 were administered at baseline and every cycle throughout treatment. Change from baseline to post-2 cycles and deterioration of HRQoL (≥10 points change) were analysed. Results: At data cut-off (March 22, 2021), 126 patients (32 in cohort 1, 47 in cohort 2, 47 in cohort 3) were included for this analysis. Compliance for QLQ was very high ( > 90 %) at all time points. C30 global health status (GHS) scores remained stable at all time points and from baseline to post 2 cycles (mean [95% CI] change, 2.66 [-1.10‒6.42]), with greater improvements observed in patients with responder (a best response of complete response (CR) or partial response (PR)) (3.60 [-1.27 to 8.47]) compared to non-responder (stable disease (SD) or progressive disease (PD) (0.66 [-5.19 to 6.51]). For the overall cohort, functioning scales also remained stable from baseline to post 2 cycles. Nausea/vomiting (8.4 [4.45 to 12.36]), dyspnea (7.28 [2.17 to 12.4]), constipation (9.24 [3.35 to 15.13]), financial difficulties (5.53 [1.65 to 9.41]) in C30 and eating (5.53 [1.65 to 9.41]), tiredness (5.42 [1.23 to 9.6]), treatment side effects (7.98 [1.15 to 14.81] in BIL21 were worse at post 2 cycles. However, pain (-7.14 [-12.24 to -2.04]), diarrhea (-4.48 [-8.86 to -0.1]) in C30 and jaundice (-5.51 [-9.26 to -1.76]), pain (-6.02 [-9.7 to -2.34] in BIL21 were improved and more improvement was shown in responder compared to non-responder. Regarding deterioration of C30 GHS, median deterioration-free survival (months [95% CI]) was 4.14 (2.66-6.47) in all cohorts and there was no difference between responder (3.68 [2.27-7.92]) and non-responder (5.59 [2.73-9.46], Hazard ratio = 1.00 [95% CI, 0.62-1.61], p = 0.997). There was no difference among 3 cohorts. Conclusions: GemCis plus D ± T in chemotherapy-naïve advanced BTC generally preserved HRQoL and improved some symptom scales such as jaundice and pain although chemotherapy related symptom scales were worse.

TPS639 Background: Pancreatic cancer (PC) is well-known as a strongly immunosuppressive tumor. The tumor microenvironment of PC play a fundamental part in maintaining a non-immunogenic and immuno-suppressive environment through the production of inhibitory cytokines and complex interaction between tumor cells, regulatory T cells, and myeloid-derived suppressor cells (Li KY et al. 2020). However, through integrated genomics and immunophenotyping, the immune-rich type had a relatively good prognosis in advanced PC (Wartenberg M et al. 2018). Based on this, various attempts have been made to apply immune checkpoint inhibitor (ICI) to PC. Disappointingly, ICI monotherapy is ineffective in most advanced PCs, and a strategy of combining ICI with ICI, chemotherapy or targeted therapy has been recently tried. However, the mechanism of immune modulation induced by ICI in combination with chemotherapy in PC is still not well-known, so biomarker studies are needed to understand the role of immunotherapy in advanced PC. Also based on this, it is expected to develop an effective ICI treatment strategy in PC. This study is a non-randomized, parallel assignment phase 2 trial aimed to explore dynamic modulation of the immune system caused by co-administration of pembrolizumab and cytotoxic chemotherapy in patients with advanced PC. Methods: Eligible patients have recurred or metastatic pancreatic cancer. Patients who have received chemotherapy for advanced PC are excluded, except for previous adjuvant chemotherapy. Patients who have received ICI are excluded. There are 2 chemotherapy cohorts (FOLFIRINOX, n=41; Gemcitabine/Nab-paclitaxel, n=36). Patients enrolled in the FOLFIRINOX cohort will receive pembrolizumab 200mg intravenously once every 3 weeks, plus FOLFIRINOX chemotherapy every 2 weeks. In Gemcitabine/Nab-paclitaxel cohort, patients will receive gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day 1, 8, 15 of a 4-week cycle, plus pembrolizumab 200mg intravenously once every 3 weeks. The primary endpoint is objective response rate, with key secondary endpoints including progression-free survival, duration of response, disease control rate, overall survival, safety, and patient-reported outcome. For evaluating metabolic response, 18F-FDG PET-CT scan will be conducted before treatment and at the first response evaluation. Tumor tissue biopsies are performed three times in total: screening, the first response evaluation, and disease progression. Blood samples are being collected every cycles for translational biomarker studies. Clinical trial information: NCT04447092.

Background: DNA damage response (DDR) pathway is essential for maintaining genomic stability, cell survival, and tumorigenesis. However, the roles of DDR pathway in HER2-positive tumors remain unclear. This study aims to discover the function of DDR in trastuzumab-resistant (TR) cells to better understand HER2-biology and to suggest novel treatment strategy using DDR-targeting agents in HER2-positive TR tumors. Methods: Four HER2-positive TR cell lines (NCI-N87TR, SNU-216TR, SNU-2670TR, and SNU-2773TR) and their corresponding parental cells (NCI-N87, SNU-216, SNU-2670, and SNU-2773) were subject to immunoblotting to identify expression profiles of DDR proteins. Proteasome inhibitor MG-132 and cycloheximide chase assay were used for understanding PARP1 dynamics in TR cells. MTT assay and colony-forming assay were performed to evaluate antiproliferative effect of PARP inhibitor (PARPi, olaparib), ATM inhibitor (ATMi, AZD0156) and ATR inhibitor (ATRi, Ceralasertib). DNA damage and homologous recombination repair (HRR) efficiency were measured by comet assay and immunofluorescence respectively. Cell cycle analysis using flow cytometry was performed to assess drug-induced apoptosis. Results: Increase of PARP1 expression was observed in all four TR cells. Decreased proteasomal degradation of PARP1 was found in TR cells compared to parental cells. Olaparib showed better anti-proliferative effect in TR cells compared to parental cells. After treating with olaparib, there was a defect in formation of Rad51 foci, instead, there was induction of phosphorylation of ATM and ATR in TR cells, which might attenuate the effects of olaparib in TR cells. Combination of olaparib with AZD0156 showed stronger anti-tumor effect than olaparib monotherapy in TR cells. Moreover, synthetic lethal interaction was observed by olaparib/AZD0156 combination in TR cells. Interestingly, this synthetic lethal interaction was exclusively occurred in TR cells not in parental cells. Even though olaparib and ceralasertib combination showed better anti-tumor effect than each single drug in some TR cells, synthetic lethal interaction was not observed by olaparib/ceralasertib combination in TR cells. Conclusion: Dual inhibition of PARP1 and ATM could be a good strategy to overcome the resistance to trastuzumab in HER2-positive cancers using its synthetic lethal interaction. Citation Format: Kyoung-Seok Oh, Ah-Rong Nam, Ju-Hee Bang, Hye-Rim Seo, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. A synthetic lethal strategy using PARP and ATM inhibition for overcoming trastuzumab-resistance in HER2-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1079.

Background: Targeting DNA damage response (DDR) has potential anti-tumor effects in diverse cancer types. Homologous-recombination DDR gene mutations are found in 28.9% of biliary tract cancer (BTC). We aimed to evaluate the anti-tumor effects of olaparib (PARP inhibitor) with or without ceralasertib (ATR inhibitor) in BTC.Methods: Ten BTC cell lines (SNU245, SNU308, SNU478, SNU869, SNU1079, SNU1196, HuCCT-1, TFK-1, SNU2670, and SNU2773) were tested to evaluate the anti-tumor effects of olaparib alone and in combination with ceralasertib. MTT assay, colony formation assay, cell cycle analysis, western blot, comet assay and co-culture with human PBMC were used as experimental methods. Tumor xenograft model was established to test olaparib with or without ceralasertib in vivo.Results: Olaparib alone showed moderate anti-proliferative effects in all BTC cells and increased p-ATR and PD-L1 expression. Olaparib plus ceralasertib showed synergistic anti-proliferative effects and led to DNA damage breaks in vitro. Ceralasertib also downregulated PD-L1 level through p-STAT3 and YAP pathway with or without human PBMC conditions. In SNU478-xenograft models, Olaparib plus ceralasertib combination significantly suppressed tumor growth and downregulated PD-L1 and YAP, compared with monotherapy. It also effectively reduced CXCR2 and CXCR4 expression. Conclusion: Combination of olaparib plus ceralasertib showed potent anti-tumor effects in BTC cells. This study could provide the preclinical evidence of development of PARP and ATR dual inhibition in BTC patients. Clinical trial using olaparib and ceralasertib combination in advanced BTC is ongoing (ClinicalTrials.gov Identifier: NCT04298021). Citation Format: Ah Rong Nam, Mei Hua Jin, Kyoung-Seok Oh, Hye Rim Seo, Jae-Min Kim, Ju-Hee Bang, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. Co-Targeting PARP and ATR in biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2073.

TPS4153 Background: Olaparib (PARP inhibitor) leads to DNA damage and cell death. In phase III study (GOLD), olaparib plus paclitaxel did not improve overall survival (OS) compared with paclitaxel in second-line gastric cancer (GC) patients with statistical significance, even though there was absolute increase of OS (Lancet Oncol 2017). This highlights the importance of biomarker-based patient selection. The changes of tumor microenvironment by paclitaxel/olaparib have not been explored. Besides DNA damage, olaparib induces positive or negative immune modulation by recruiting T cells, promoting type I interferon and upregulating PD-L1, which suggests anti-PD (L1) inhibitor plus olaparib could enhance anti-tumor immunity. Combination of Anti-PD-1 agents with chemotherapy showed a good clinical efficacy in first-line of GC compared with chemotherapy alone (Checkmate 649). Based on these findings, the combination of paclitaxel/olaparib/anti-PD(L1)1 inhibitor, with different mode of actions, might enhance antitumor activity. This is phase II study of paclitaxel/olaparib/durvalumab combination in second-line GC patients, to find out immune modulation effects by paclitaxel/olaparib combination, and to see the efficacy, safety, optimal biomarkers for this combination. Methods: All patients with histologically confirmed unresectable GC have failed to prior one chemotherapy and measurable lesion. Prior exposure to anti-PD(L1)1, PARP inhibitor is excluded. At 1st cycle, paclitaxel (80 mg/m2) on D1, 8 and 15 and olaparib (150 mg bid) on D1-28 is administered. Pre-treatment biopsy and after first cycle biopsy is done. From second cycle, durvalumab 1500 mg on D1 every 4 weeks is added. At the time of disease progression, tumor biopsy is mandatory. Blood samples for biomarkers should be obtained every cycles. Response evaluation is performed after first 3 cycles and repeated every 2 cycles. Primary endpoint is the disease control rate (the percentage of patients who have achieved complete or partial remission, stable disease based on RECIST v1). Key secondary endpoints are overall response rate, progression-free survival, OS, quality of life and safety. Clinical trial information: NCT03579784.

TPS4166 Background: Ceralasertib (AZD6738) is a selective ATR inhibitor that causes stalled replication forks to collapse, leading to accumulation of double-strand DNA breaks, which is expected to have synergistic anti-tumor effects with immune checkpoint inhibitors (ICI) or PARP inhibitors. First, accumulation of DNA damage by ceralasertib induces tumor cell death, leads to the release of tumor-specific antigen, changing the tumor microenvironment to promote antigen presentation and enhances the anti-tumor effect of ICI. Second, by simultaneously inhibiting two DNA-damage response (DDR) pathways downstream of PARP and ATR, cancer cells are unable to repair damaged DNA, leading to cell death. Ceralasertib has demonstrated promising anti-tumor activity and manageable toxicity in combination with durvalumab or olaparib in solid tumors in a phase 1 study (NCT02264678). In preclinical studies, ceralasertib has shown potent anti-tumor effects in biliary tract cancer (BTC) as a monotherapy and in combination with chemotherapy (Nam, et al, 2019). Methods: This is an open-label, phase 2 umbrella study assessing the efficacy of ceralasertib in combination with durvalumab or olaparib in patients with advanced BTC. Eligible patients have histologically confirmed BTC (including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), have failed at least one chemotherapy and have ECOG performance status of 0-1. Patients who have received prior ICI, ATR or PARP inhibitor are excluded. Each cycle consists of 4 weeks. In ceralasertib /durvalumab cohort, 37 patients will receive durvalumab 1.5g on day 1 and ceralasertib 240mg twice daily on days 15-28. In ceralasertib /olaparib cohort, 37 patients receive ceralasertib 160mg once daily on days 1-7 and olaparib 300mg twice daily on days 1-28. The primary endpoint is disease control rate, with key secondary endpoints including overall response rate, progression-free survival, overall survival, and safety. Tissue and blood samples are being collected for translational biomarker studies. Clinical trial information: NCT04298021.

Background: Trastuzumab in combination with chemotherapy is a standard of care for patients with HER2-positive breast and gastric cancer. Resistance mechanism to trastuzumab, anti-HER2 therapy, includes multiple pathways. Cancer cells could evade immune surveillance through high expression of programmed cell death ligand 1 (PD-L1) on cancer or immune cells. Among resistance mechanisms to trastuzumab, the role of PD-L1 modulation has not yet been discovered in HER2-positive cancers. WEE1 is involved in cell cycle progression and DNA damage response (DDR), and, interestingly, beyond DDR, it could modulate immunes. We aimed to evaluate the role of PD-L1 in trastuzumab resistance in HER2-positive cancers with/without immune cells and to explore WEE1 inhibitor as a trastuzumab resistance overcoming strategy by modulation of PD-L1. Methods: Four trastuzumab-resistant (HR) cells (SNU216HR, N87HR, SNU2670HR, SNU2773HR) were established from 2 HER2-amplified gastric cancer cells (SNU216, NCI-N87) and 2 HER2-amplified biliary tract cancer cells (SNU2670, SNU2773). For WEE1 inhibition, AZD1775 was used. MTT assay, colony formation assay, cell cycle analysis by FACS Calibur flow cytometer, and western blot were done. Results: All four HR cells showed PD-L1 upregulation compared with parental cells. When PD-L1 was knocked-down by transfection with si-PD-L1, anti-growth/proliferation effects were observed in MTT assay and colony forming assay. PD-L1 itself may promote cancer cell growth without interacting with immune cells. AZD1775 downregulated PD-L1 expression and induced cell cycle arrest at sub-G1 and G2/M phases in all 4 HR cells. The synergistic anti-proliferative effects were found in all 4 HR cells with co-treatment of trastuzumab and AZD1775. Conclusion: PD-L1 upregulation may contribute to trastuzumab resistance in HER2-positive cancer cells. Targeting WEE1-PD-L1 pathway might be a candidate strategy to overcome trastuzumab resistance in HER2-positive cancers. Citation Format: Meihua Jin, Ah-Rong Nam, Ji-Eun Park, Ju-Hee Bang, Kyoung-Seok Oh, Do-Youn Oh, Yung-Jue Bang. WEE1 inhibition could reverse trastuzumab resistance by downregulation of PD-L1 in HER2-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2110.

4034 Background: The soluble form Programmed Death-Ligand 1(sPDL1) is suggested to have immunosuppressive activity and under investigation as candidate biomarker for immuno-oncology drug development. In this study, we measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in advanced gastric cancer (GC). Methods: We prospectively enrolled 68 GC patients who were candidates for palliative standard 1st-line chemotherapy, and blood was serially collected at pre-and post-one cycle of chemotherapy, at best response and disease progression. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS), progression-free survival (PFS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were obtained. The cut-off values of sPDL1 levels and changes for survivals were found using C-statistics. Results: The median baseline sPDL1 was 0.8ng/mL(range, 0.06 - 6.06ng/mL). The median OS and PFS were 14.9 months (95% CI: 7.33-22.47) and 8.0 months (95% CI: 5.96-10.0), respectively. sPDL1 and NLR showed a positive correlation. Patients with low levels of sPD-L1 at diagnosis ( < 1.92 ng/mL) showed a better OS and PFS than the patients with a high sPDL1 (OS: 18.3 vs. 95 months, P = 0.057, PFS: 8.9 vs. 6.0 months, P = 0.04). The baseline sPDL1 before treatment were higher in the PD group than in the SD and PR groups (mean:2.91, 1.17, 1.19, P = 0.019). Patients whose sPDL1 increased after 1st cycle of chemotherapy showed the tendency of worse PFS and OS. When disease progressed, sPDL1 increased compared with baseline (mean:1.31, 1.45, P = 0.029). Conclusions: sPDL1 at pre-chemotherapy confers the prognostic value for PFS and OS in GC patients under palliative 1st-line chemotherapy. The dynamics of sPDL1 during chemotherapy correlates with disease courses.

4094 Background: We previously reported that soluble programmed death-Ligand 1 (sPD-L1) at pre-chemotherapy indicated the prognostic value for overall survival (OS) and the dynamics of sPD-L1 during palliative chemotherapy correlated with disease burden in biliary tract cancer (BTC). Transforming growth factor (TGF) -β attenuates tumor response to PD1/PD-L1 inhibitors. Strategy of dual targeting of PD1/PD-L1 and TGF-β is now under investigation. This study aimed to evaluate the association between soluble TGF-β (sTGF-β) and sPD-L1, dynamics during chemotherapy and its prognostic role in BTC. Methods: Study population consisted of 90 BTC patients treated with first line chemotherapy. Blood samples at pre-and post-chemotherapy and at disease progression (PD) were prospectively collected. Plasma sTGF-β and sPD-L1 levels were measured by using an enzyme-linked immunosorbent assay. Results: The median progression free survival (PFS) and OS of all patients was 6.9 months (m) (95% CI, 5.2-8.6) and 11.5 m (95% CI, 9.4-13.6). The best response was CR in 7 (7.8%), PR in 20 (22.2%), SD in 52 (57.8%), and PD in 11 patients (12.2%). The mean baseline sTGF-β and sPD-L1 were 16.4 ng/ml and 1.3 ng/ml. There was a positive association between sTGF-β and sPD-L1 in terms of baseline levels and changes after chemotherapy (at pre-chemo, Pearson correlation = 0.578, p < 0.001; change after chemotherapy, Pearson correlation = 0.542, p < 0.001). Patients with higher pre-chemotherapy sPD-L1 ( > 1.3 ng/ml) showed worse OS (9.2 vs 16.2 m, p < 0.001). Both sPD-L1 (1.8 vs 1.0 ng/ml, p < 0.001) and sTGF-β (20.5 vs 11.6 ng/ml, p < 0.001) were increased significantly at the time of PD compared with pre-chemotherapy. Regarding changes after chemotherapy, increased sTGF-β after chemotherapy (Δ > 3.2 ng/ml) had worse prognosis (PFS: 5.1 vs 7.3 m, p = 0.024; OS: 9.2 vs 12.3 m, p = 0.028). This prognostic value of change of sTGF-β after chemotherapy was also significant in multivariable analysis with other clinical factors (PFS: HR = 1.78, p = 0.022; OS: HR = 1.86, p = 0.018). Conclusions: In BTC, there is a positive association between sTGF-β and sPD-L1 value in terms of baseline levels and changes after chemotherapy. sTGF-β could be associated with the survival, particularly, increased value after chemotherapy indicates worse prognosis.

This paper investigates the relationship between R&D capabilities (learning, R&D and external networking), technology commercialization (manufacturing and marketing), and innovation performance (product competitiveness) among SMEs in IT-related businesses. The study focuses on 254 Korean IT SMEs that were either recipients of government R&D grants or their indirect beneficiaries during the two-year period between 2005 and 2007. The major findings of this study are as follows: First, unlike what has been suggested by previous studies, R&D intensity was not the only factor influencing the innovation performance of firms; learning and external networking also had a significant influence on innovation. The research implication of this finding is that the measurement of firms’ performance should not be solely based on the intensity of R&D expenditures, but a broader set of factors including learning and external networking capabilities. Second, the technology commercialization capabilities of firms played the role of a mediator in the relationship between R&D and innovation performance. Within the innovation cycle of input (R&D capabilities), process (technology commercialization capabilities) and output (innovation performance), we found that R&D seldom influenced performance in a direct fashion, but its influence was most often mediated by technology commercialization capabilities. The practical implication of this finding for companies is that in order to improve performance, they must avoid narrowly focusing on R&D, but must invest also in capabilities to commercialize technologies resulting from R&D. Third, when direct and indirect beneficiaries of public R&D funding are compared together, the explanatory power of the relationship between R&D capabilities, technology commercialization capabilities and innovation performance was stronger among the latter than the former. Santrauka Straipsnyje tiriamas ryšys tarp mokslinių tyrimų ir eksperimentinės plėtros (MT ir EP), technologijų komercializavimo (gamybos ir rinkodaros) bei inovacijų efektyvumo (produkto konkurencingumo) smulkiose ir vidutinėse informacinių technologijų (IT) įmonėse. Buvo tiriamos 254 Korėjos smulkios ir vidutinės IT įmonės, kurios buvo valstybės paramos gavėjos arba gavo netiesioginę paramą 2005–2007 m. Pagrindinės tyrimo išvados yra šios: mokslinių tyrimų ir eksperimentinės plėtros mastas nėra vienintelis veiksnys, darantis įtaką inovacijų efektyvumui įmonėse; mokymas ir išorinis komunikavimas taip pat daro didelę įtaką inovacijoms. Taigi įmonių veiklos vertinimas neturėtų būti grindžiamas tik mokslinių tyrimų ir eksperimentinės plėtros intensyvumu, bet ir kitais veiksniais, kaip mokymo ir išorinio komunikavimo galimybės. Įmonės turėtų investuoti į galimybes komercializuoti technologijas, sukurtas mokslinių tyrimų ir eksperimentinės plėtros metu. First published online18 Jan 2012 Reikšminiai žodžiai:technologijų komercializavimas,inovacijų efektyvumas,moksliniai tyrimai ir eksperimentinė veikla

This paper investigates the relationship between RD learning and external networking also had a significant influence on innovation. The research implication of this finding is that the measurement of firms' performance should not be solely based on the intensity of R&D expenditures, but a broader set of factors including learning and external networking capabilities. Second, the technology commercialization capabilities of firms played the role of a mediator in the relationship between R&D and innovation performance. Within the innovation cycle of input (R&D capabilities), process (technology commercialization capabilities) and output (innovation performance), we found that R&D seldom influenced performance in a direct fashion, but its influence was most often mediated by technology commercialization capabilities. The practical implication of this finding for companies is that in order to improve performance, they must avoid narrowly focusing on R&D, but must invest also in capabilities to commercialize technologies resulting from R&D. Third, when direct and indirect beneficiaries of public R&D funding are compared together, the explanatory power of the relationship between R&D capabilities, technology commercialization capabilities and innovation performance was stronger among the latter than the former. This result suggests that indirect technology support toward Korean IT SMEs through government-sponsored research institutions is a more effective way of allocating public R&D funds than direct funding in the form of grants to individual companies. In other words, sponsoring R&D projects at research organizations with high-quality manpower and equipment and facilities like government research institutions, which are more likely to result in technologies that are readier for commercialization and have greater value-added, and transferring resulting technologies to small and medium-size ventures is a better strategy for enhancing national technological competitiveness in IT.