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Slow-cycling/dormant cancer cells (SCCs) have pivotal roles in driving cancer relapse and drug resistance. A mechanistic explanation for cancer cell dormancy and therapeutic strategies targeting SCCs are necessary to improve patient prognosis, but are limited because of technical challenges to obtaining SCCs. Here, by applying proliferation-sensitive dyes and chemotherapeutics to non-small cell lung cancer (NSCLC) cell lines and patient-derived xenografts, we identified a distinct SCC subpopulation that resembled SCCs in patient tumors. These SCCs displayed major dormancy-like phenotypes and high survival capacity under hostile microenvironments through transcriptional upregulation of regulator of G protein signaling 2 (RGS2). Database analysis revealed RGS2 as a biomarker of retarded proliferation and poor prognosis in NSCLC. We showed that RGS2 caused prolonged translational arrest in SCCs through persistent eukaryotic initiation factor 2 (eIF2α) phosphorylation via proteasome-mediated degradation of activating transcription factor 4 (ATF4). Translational activation through RGS2 antagonism or the use of phosphodiesterase 5 inhibitors, including sildenafil (Viagra), promoted ER stress-induced apoptosis in SCCs in vitro and in vivo under stressed conditions, such as those induced by chemotherapy. Our results suggest that a low-dose chemotherapy and translation-instigating pharmacological intervention in combination is an effective strategy to prevent tumor progression in NSCLC patients after rigorous chemotherapy.

Purpose: Histone deacetylase inhibitors (HDI) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study.Experimental Design: The methylation status of CCCTC-binding factor (CTCF)-binding sites in the IGF2/H19 imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing. The effectiveness of single or combinatorial blockade of DNA methyltransferase 1 (DNMT1) and histone deacetylase (HDAC) was evaluated using cell viability assay and patient-derived tumor xenograft (PDX) model.Results: HDAC inhibition by vorinostat increased acetylated STAT3 (K685), resulting in transcriptional upregulation of DNMT1. DNMT1-mediated hypermethylation of CTCF-binding sites in the IGF2/H19 ICR decreased CTCF insulator activity, leading to a transcriptional upregulation of IGF2 and activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway in cells with acquired or de novo vorinostat resistance. Strategies targeting DNMT1 diminished the IGF2 expression and potentiated vorinostat sensitivity in preclinical models of lung cancer with hypermethylation in the H19/IGF2 ICR. The degree of ICR hypermethylation correlated with vorinostat resistance in patient-derived lung tumors and in patients with hematologic malignancies.Conclusions: DNMT1-mediated transcriptional upregulation of IGF2 is a novel mechanism of resistance to HDIs, highlighting the role of epigenetic deregulation of IGF2 in HDI resistance and the potential value of the H19/IGF2 ICR hypermethylation and DNMT1 expression as predictive biomarkers in HDI-based anticancer therapies. Clin Cancer Res; 23(5); 1299–311. ©2016 AACR.

Supplementary Methods Supplementary Table S1. Enhanced phosphorylation of several protein kinases such as IGF-1R and Akt in vorinostat-resistant H1944R compared to its parental control (H1944). Supplementary Table S2. Synergistic effect of combinatorial treatment with erlotinib and linsitinib in H1944R cells. Supplementary Table S3. Primer sequences used for MSP. Supplementary Table S4. Primer sequences used for ChIP analysis. Supplementary Table S5. Primer sequences used for RT-PCR analysis.

Supplementary Figure S1. The involvement of the IGF-1R activation in acquired resistance to vorinostat. Supplementary Figure S2. Differential regulation of the CTCF binding to the CTCF6 site in the H19/IGF2 ICR according to vorinostat sensitivity. Supplementary Figure S3. Enhanced apoptosis by combinatorial treatment with vorinostat and Stattic. Supplementary Figure S4. The association of DNMT1 expression with vorinostat sensitivity in lymphoma cell lines.

Slow-cycling cancer cells (SCCs) with a quiescence-like phenotype are believed to perpetrate cancer relapse and progression. However, the mechanisms that mediate SCC-derived tumor recurrence are poorly understood. Here, we investigated the mechanisms underlying cancer recurrence after chemotherapy, focusing on the interplay between SCCs and the tumor microenvironment. We established a preclinical model of SCCs by exposing non-small-cell lung cancer (NSCLC) cells to either the proliferation-dependent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) or chemotherapeutic drugs. An RNA sequencing analysis revealed that the established SCCs exhibited the upregulation of a group of genes, especially epidermal growth factor (EGF). Increases in the number of vascular endothelial growth factor receptor (VEGFR)-positive vascular endothelial cells and epidermal growth factor receptor (EGFR) activation were found in NSCLC cell line- and patient-derived xenograft tumors that progressed upon chemotherapy. EGFR tyrosine kinase inhibitors effectively suppressed the migration and tube formation of vascular endothelial cells. Furthermore, activating transcription factor 6 (ATF6) induced the upregulation of EGF, and its antagonism effectively suppressed these SCC-mediated events and inhibited tumor recurrence after chemotherapy. These results suggest that the ATF6-EGF signaling axis in SCCs functions to trigger the angiogenesis switch in residual tumors after chemotherapy and is thus a driving force for the switch from SCCs to actively cycling cancer cells, leading to tumor recurrence.

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.

Additional file 1: Figure S1 The scheme for classifying CSC and non-CSC populations from CRC cells. Figure S2. GTP-loaded active RAS levels are highly elevated with the levels of RAS in CSC-like CRC cells compared with non-CSC cells. Figure S3. Effects of KYA1797K on CSC properties of CRC cells harboring APC and KRAS mutations. Figure S4. Apc and Kras mutations synergistically activate the CSC properties in murine small intestinal tumor cells. FACS analyses of CD44 and CD133 double-positive cells. Figure S5. LGR5+ CSCs intermingled with paneth cells which secrete EGF, R-spondin1, and Noggin were more activated than LGR5+ CSCs not intermingled with paneth cells. Figure S6. Effect of KYA1797K on suppression of CSC properties in small intestinal tumors of ApcMin/+/ K-rasLA2. Figure S7. KYA1797K significantly induces the KRT20 in CRC PDTX. Table S1. Effects of KYA1797K on CSC populations of CRC cells. Alteration of CSC marker positive cells by KYA1797K treatment were analyzed by flow cytometry. Table S2. Genetic profiles of PDC. The mutation status of APC, PIK3CA, KRAS, EGFR, PI3K, and TP53 in PDCs

Simple Summary Local invasion and distal metastasis are the main causes of cancer-related death and the poor prognosis of patients with aerodigestive tract cancers. Therefore, understanding the biology of invasion and metastasis is important for the development of effective therapeutic strategies. The present study shows that insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the migration and invasion of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cells in vitro and the development of metastasized tumors in vivo. Mechanistic studies suggest vimentin as a cellular target for the antimetastatic effect of IGFBP-3. These results contribute to a better understanding on the regulation of metastasis of cancer cells, providing the rationale to utilize IGFBP-3 as an effective therapeutic strategy targeting migration and metastasis of aerodigestive tract cancers. Abstract The proapoptotic, antiangiogenic, and antimetastatic activities of insulin-like growth factor binding protein-3 (IGFBP-3) through IGF-dependent or -independent mechanisms have been suggested in various types of human cancers. However, a mechanistic explanation of and downstream targets involved in the antimetastatic effect of IGFBP-3 is still lacking. In this study, by applying various in vitro and in vivo models, we show that IGFBP-3 suppresses migration and invasion of human head and neck squamous carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cells. Silencing IGFBP-3 expression elevated the migration and invasion of NSCLC and HNSCC cells in vitro and their local invasion and metastasis in vivo, whereas overexpression of IGFBP-3 decreased such prometastatic changes. Local invasion of 4-nitroquinoline-1-oxide (4-NQO)-induced HNSCC tumors was consistently significantly potentiated in Igfbp3 knockout mice compared with that in wild-type mice. Mechanistically, IGFBP-3 disrupted the protein stability of vimentin via direct binding and promoting its association with the E3 ligase FBXL14, causing proteasomal degradation. The C-terminal domain of IGFBP-3 and the head domain of vimentin are essential for their interaction. These results provide a molecular framework for IGFBP-3′s IGF-independent antimetastatic and antitumor activities.

Purpose: Histone deacetylase inhibitors (HDI) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study. Experimental Design: The methylation status of CCCTC-binding factor (CTCF)-binding sites in the IGF2/H19 imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing. The effectiveness of single or combinatorial blockade of DNA methyltransferase 1 (DNMT1) and histone deacetylase (HDAC) was evaluated using cell viability assay and patient-derived tumor xenograft (PDX) model. Results: HDAC inhibition by vorinostat increased acetylated STAT3 (K685), resulting in transcriptional upregulation of DNMT1. DNMT1-mediated hypermethylation of CTCF-binding sites in the IGF2/H19 ICR decreased CTCF insulator activity, leading to a transcriptional upregulation of IGF2 and activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway in cells with acquired or de novo vorinostat resistance. Strategies targeting DNMT1 diminished the IGF2 expression and potentiated vorinostat sensitivity in preclinical models of lung cancer with hypermethylation in the H19/IGF2 ICR. The degree of ICR hypermethylation correlated with vorinostat resistance in patient-derived lung tumors and in patients with hematologic malignancies. Conclusions: DNMT1-mediated transcriptional upregulation of IGF2 is a novel mechanism of resistance to HDIs, highlighting the role of epigenetic deregulation of IGF2 in HDI resistance and the potential value of the H19/IGF2 ICR hypermethylation and DNMT1 expression as predictive biomarkers in HDI-based anticancer therapies. Clin Cancer Res; 23(5); 1299–311. ©2016 AACR.

The epidermal growth factor receptor (EGFR) inhibitors such as erlotinib and gefitinib are widely used for treatment of non-small cell lung cancer (NSCLC), but they have shown limited efficacy in an unselected population of patients. The KRAS mutations, which are identified in approximately 20% of NSCLC patients, have shown to be associated with the resistance to the EGFR tyrosine kinase inhibitors (TKIs). Currently, there is no clinically available targeted therapy which can effectively inhibit NSCLC tumors harboring KRAS mutations. This study aims to show the effectiveness of KYA1797K, a small molecule which revealed anti-cancer effect in colorectal cancer by destabilizing Ras via inhibiting the Wnt/β-catenin pathway, for the treatment of KRAS-mutated NSCLC. While erlotinib fail to have anti-transforming effect in NSCLC cell lines harboring KRAS mutations, KYA1797K effectively inhibited the Ras-ERK pathway in KRAS-mutant NSCLC cell lines. As a result, KYA1797K treatment suppressed the growth and transformation of KRAS mutant NSCLC cells and also induced apoptosis. Furthermore, KYA1797K effectively inhibited Kras-driven tumorigenesis in the KrasLA2 mouse model by suppressing the Ras-ERK pathway. The destabilization of Ras via inhibition of the Wnt/β-catenin pathway is a potential therapeutic strategy for KRAS-mutated NSCLC that is resistant to EGFR TKI.

In this study, operation data from an actual plant in M city were analyzed to evaluate effects of water supply into sewage sludge on the co-incineration of municipal solid waste (MSW) and sewage sludge. Design capacity of the stoker incinerator is 50 m/day. Maximum portion of sewage sludge in the total waste input was 20%. According to this research, moisture content increase up to 85% of sewage sludge could be possible by water supply on MSW input to the incinerator. Therefore, stable operation of incinerator could be achieved. As water was added into sewage sludge up to 85%, input quantity of sewage sludge to frequency (Hz) was similar to theoretical input. Also, it is concluded that stable management of incinerator without leachate combustion and damages of refractory bricks and castable could be achieved by the reduction of low heating value.

The various promotion countermeasures such as solidification, carbonization, and the creation of cement materials have been considered to existing treatment methods such as incineration and the creation of composts, since direct landfill was prohibited for encouraging the recycling based on the sludge treatment on land. The Main objective of this study is to investigate the feasibility of co-incineration for MSW (municipal solid waste) and SS (sewage sludge) through the quantitative supply of sewage sludge. In this study, optimum water content to operate normally incinerator is 85%. In order to increase the workability of sewage sludge, it is necessary to supply properly water. In the case study of sites, optimum water content is 87% due to the water evaporation. Therefore, it was found that the water content up to 87% would be reached the stable operation of co-incinerator on the mixture of municipal waste solid and sewage sludge.

The various promotion countermeasures such as solidification, carbonization, and the creation of cement materials have been considered to existing treatment methods such as incineration and the creation of composts, since direct landfill was prohibited for encouraging the recycling based on the sludge treatment on land. The Main objective of this study is to investigate the feasibility of co-incineration for MSW (Municipal Solid Waste) and SS (Sewage Sludge) through the change of heat and atmospheric pollutants. In this study, LHV (Low Heating Value) is 100~300 kcal/kg because the MC (Moisture Content) of de-hydrated sewage sludge is approximately 80%. From the results, we knew the feasibility of co-incineration for MSW (80%) and SS (20%). As the co-incineration rate of SS up to 20% became higher, the loading of heat and atmospheric pollutants was not influenced.

Cancer stem-like cells (CSCs) contribute to tumor recurrence and chemoresistance. Hence, strategies eradicating CSCs are crucial for effective anticancer therapies. Here, we demonstrate transcriptional upregulation of the heat shock proteins (Hsp90 and Hsp70) and their co-chaperones and enhanced activities of the Hsp system in both non-CSCs and CSCs in non-small cell lung cancer (NSCLC) cells. Genetic and pharmacologic strategies targeting Hsps eliminated both CSCs and non-CSCs of NSCLC, suggesting the functional role of the Hsp system in the two populations in NSCLC. We further identified Compound A, a natural product-derived compound, as a novel Hsp70 inhibitor eliminating both the CSC and non-CSC populations in NSCLC. Compound A inhibited the sphere-forming ability of NSCLC CSCs by inducing apoptosis. Compound A also suppressed the viability and colony-forming abilities of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance by inducing apoptosis with minimal toxicity in normal cells derived from various organs. Mechanistically, Compound A disrupted Hsp70 function by binding to the ATP-binding pockets of Hsp70. These data suggest the rationale to target the Hsp system for controlling both CSCs and non-CSCs in NSCLC and the potential of Compound A as a natural Hsp70 inhibitor to eliminate the two populations with limited toxicities. Citation Format: Seung Yeob Hyun, Huong T. Le, Jaebeom Cho, Hye-Young Min, Ho-Young Lee. A natural product-derived Compound A effectively targets both cancer stem and non-stem cells in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2677.

In this study, the effect of moisture supply during desiccation in a landfill liner system under the climatic conditions prevalent in spring and summer in Korea was investigated. The specimens used in the test were a mixture of dredged clay (parent soil) combined with additives Pa or Pb (proprietary cementing materials — Pa is mostly silicate powder and Pb is mostly quicklime). The mixing ratio of the dredged clay to Pa was 5: 1 and that for dredged clay to Pb was 20: 3 (w/w). The effect of moisture supply to the liner system was evaluated in three ways: the uniaxial compressive strength, permeability, and shrinkage tests during desiccation. From the results, the compressive strength of the Pa/Pb-clay mixture without moisture supply decreased more dramatically than that of the Pa/Pb-clay mixture with moisture supply during desiccation. The permeability of the latter decreased more rapidly than that of the former. Shrinkage of the Pa/Pb-clay mixture with moisture supply during the curing process was less than that of the Pa/Pb-clay mixture without moisture supply.

Background Therapeutic interventions in the insulin-like growth factor receptor (IGF-1R) pathway were expected to provide clinical benefits; however, IGF-1R tyrosine kinase inhibitors (TKIs) have shown limited antitumor efficacy, and the mechanisms conveying resistance to these agents remain elusive. Methods The expression and activation of the IGF-1R and Src were assessed via the analysis of a publicly available dataset, as well as immunohistochemistry, Western blotting, RT-PCR, and in vitro kinase assays. The efficacy of IGF-1R TKIs alone or in combination with Src inhibitors was analyzed using MTT assays, colony formation assays, flow cytometric analysis, and xenograft tumor models. Results The co-activation of IGF-1R and Src was observed in multiple human NSCLC cell lines as well as in a tissue microarray (n = 353). The IGF-1R and Src proteins mutually phosphorylate on their autophosphorylation sites. In high-pSrc-expressing NSCLC cells, linsitinib treatment initially inactivated the IGF-1R pathway but led a Src-dependent reactivation of downstream effectors. In low-pSrc-expressing NSCLC cells, linsitinib treatment decreased the turnover of the IGF-1R and Src proteins, ultimately amplifying the reciprocal co-activation of IGF-1R and Src. Co-targeting IGF-1R and Src significantly suppressed the proliferation and tumor growth of both high-pSrc-expressing and low-pSrc-expressing NSCLC cells in vitro and in vivo and the growth of patient-derived tissues in vivo. Conclusions Reciprocal activation between Src and IGF-1R occurs in NSCLC. Src causes IGF-1R TKI resistance by acting as a key downstream modulator of the cross-talk between multiple membrane receptors. Targeting Src is a clinically applicable strategy to overcome resistance to IGF-1R TKIs. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0392-3) contains supplementary material, which is available to authorized users.

Although dendritic cells (DCs) are unrivaled for initiation of immune responses, the immunomodulatory capacity of chemically fixed DC has not been thoroughly evaluated. We monitored the tolerogenic capacity of chemically fixed DCs using allogeneic heart transplantations. Bone marrow progenitors were differentiated into immature DCs which were then chemically fixed and injected intravenously into recipient mice at 14 days before allogeneic heart transplantation. Chemically fixed DCs markedly prolonged graft survival in the major histocompatibility complex (MHC) I/II mismatch cardiac transplantation (B6 --> B10.A; median survival time [MST] 12.5 days vs >70 days). T cells that encountered chemically fixed DCs showed attenuated apoptotic cell death and inactivated phenotypes after allogeneic heterotropic heart transplantation. Furthermore, when DCs from interleukin (IL)-10-/- mice were treated, the in vitro T-cell response was greater than that from IL-12-/- mice. We have suggested that the chemically fixed DCs may mediate peripheral T-cell tolerance, with therapeutic potential for allogeneic transplantation.

Lung cancer is the leading cause of the cancer-related death worldwide. Despite extensive efforts for the cure of lung cancer, the effectiveness of currently available therapeutic regimens has been marginal and limited, and recurrence is still an inevitable consequence of anticancer therapies. Therefore, mechanistic understanding on the progression and relapse of lung cancer and finding out relevant targets are essential for development of efficacious therapeutic strategies. We have investigated mechanisms of chemoresistance by using subsets of lung cancer cell lines carrying acquired resistance to chemotherapies. These chemoresistant sublines of NSCLC cells exhibited a prominent downregulation of in vitro tumor activities, including proliferation, metabolism, and protein synthesis, but displayed increased tumor growth in vivo. Additional studies revealed that the chemoresistant sublines experienced increased secretion of various soluble factors that led to increases in proliferation and stemness of drug-naïve cancer cells and recruitment of macrophages, establishing tumor microenvironment (TME) prone to tumor recurrence. We further demonstrate a pivotal role of regulator of G protein signaling 2 (RGS2) in tumor-promoting cell-cell communications, ultimately leading to chemoresistance. RGS2 disrupted chemotherapy-induced apoptosis and secretion of soluble factors involved in cellular communications in TME by regulating unfolded protein responses, a typical cellular event associated with downregulation of protein synthesis. Mechanistically, RGS2 induced proteasome-mediated protein degradation of a component of eukaryotic translation initiation factor complexes through direct interaction, resulting in blockade of the CAP-dependent protein translation. RGS2 expression was elevated in tumors derived from patients with lung cancer compared with normal counterparts and significantly associated with poor clinical outcomes. These findings suggest that RGS2 is a novel biomarker responsible for chemoresistance by establishing tumor-promoting TME and can be a potential therapeutic target for the treatment of lung cancer with chemoresistance. Citation Format: Hye-Young Min, Shin-Hyung Park, Ho Jin Lee, Jaebeom Cho, Myungkyung Noh, Seung Yeob Hyun, Ho-Young Lee. ER-stress induced translational regulation by RGS2 leads to tumor-promoting microenvironment and chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3188. doi:10.1158/1538-7445.AM2017-3188

Colorectal cancer (CRC) is a major type of human cancers in terms of incidence and mortality worldwide. Chemotherapy is one of the standard protocols for the treatment of CRC but drug resistance is recognized as the main cause of treatment failure. Resistance to anticancer therapy is a multifactorial event involving a number of interrelated or independent mechanisms. Growing evidence supports a critical role of cancer stem cell (CSC) in development, progression, and resistance to anticancer therapies in CRCs. However, the molecular and cellular mechanisms underlying the CSC's chemoresistance are not completely defined, and a comprehensive understanding of the biology of the CSCs is urgently needed. We have investigated mechanisms of chemoresistance, focusing on those mediated by CSCs, through the employment of CRC stem-like cell populations that are: 1) sorted out by using well-characterized stemness markers; ii) established via serial passage through increasing doses of oxaliplatin or 5-FU; or iii) enriched by culturing in sphere forming condition. We then assessed changes involved in CSC maintenance and found a novel role of S100A14 in CSCs of CRC. We found that transcriptional down-regulations of S100A14 expression conferred phenotypes of CSCs in the stem-like cell populations of CRC. Consistently, elevation of S100A14 expression sensitized the stem-like cell populations to the treatment with 5-FU in vitro and in vivo. Mechanistically, S100A14 directly interacted with STAT3 and promoted its degradation via the ubiquitin-proteasome pathway, leading to decreases in STAT3 target gene expression and colony forming capacity of the stem-like cell populations. Further, S100A14 expression was markedly downregulated in human CRC tissue specimens compared with their normal counterparts. Moreover, the expression level of S100A14 was inversely correlated with clinical outcomes in patients with CRC. These results collectively suggest that S100A14 is a novel target for the treatment of colorectal cancer by targeting CSCs. Citation Format: Jaebeom Cho, Hye-Young Min, Ji-Sun Lee, Ho-Young Lee. Crucial role of S100A14 in blocking cancer stem cells and sensitizing to chemotherapy through STAT3 destabilization in human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4780. doi:10.1158/1538-7445.AM2017-4780

Insulin-like growth factor I receptor (IGF-1R)-mediated signaling plays an important role in the proliferation, survival, and metastasis of cancer cells. The IGF-1R-targeting anticancer agents including monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) have been developed, but their antitumor effects have been marginal and limited in clinical trials. Therefore, the mechanism underlying resistance to the IGF-1R-targeting therapies and the rational combination strategies to overcome potential drug resistance need to be investigated. In this study, we demonstrated the association of Src with the resistance to the IGF-1R TKI in non-small cell lung cancer (NSCLC). We found the co-activation of IGF-1R/IR and Src in various human NSCLC cell lines, The mRNA expression and phosphorylation of IGF-1R and Src were also significantly correlated with each other in NSCLC databases from a public dataset and a tissue microarray (n=353). Next, we found Src can be activated through multiple pathways including EGFR and integrin β3 signaling and function as an alternative kinase for phosphorylation of IGF-1R, especially at Tyr1135/36, but not Tyr1131. Src is activated in lung cancer cells possessing both primary and acquired resistance to an IGF-1R TKI. Consistent with the results, inhibition of Src significantly attenuated activation of IGF-1R/IR and co-targeting of IGF-1R and Src effectively suppressed cell proliferation, colony formation, and tumor growth in vitro and in vivo. Taken together, these results suggest that Src causes resistance to IGF-1R TKIs by functioning as a key downstream modulator of multiple signaling pathways for IGF-1R phosphorylation and thus co-targeting IGF-1R and Src could be an effective therapeutic strategy for NSCLC. Citation Format: Hye-Young Min, Hye Jeong Yun, Hyo-Jong Lee, Jaebeom Cho, Hyun-Ji Jang, Kyung Min Kim, Woo-Young Kim, Seung-Hyun Oh, Diane Liu, J. Jack Lee, Waun Ki Hong, Ignacio I. Wistuba, Ho-Young Lee. Targeting the insulin-like growth factor receptor/Insulin receptor and Src signaling network for the treatment of non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1716. doi:10.1158/1538-7445.AM2014-1716