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Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

Background: KRAS, NRAS, and BRAF gene mutations are the most clinically relevant and frequently reported in colorectal cancer (CRC). Although data on these genes are frequently reported in several counties, data specific to these genes among Thai population are scarce. The aim of this study was to investigate and identify molecular alterations associated with colon cancer in Thai population, and to determine the impact of these genetic aberrations on clinical outcome. Methods: DNA from 108 archived formalin-fixed, paraffin-embedded (FFPE) tissue samples that histologically confirmed adenocarcinoma of stage II-III colon cancer between 2010 and 2012 at Siriraj Hospital (Bangkok, Thailand) were extracted. Gene mutational analysis was performed by next-generation sequencing (NGS) using an Oncomine Solid Tumor DNA kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA). Results: A total of 22 somatic gene mutations were detected. The mutation frequency observed in KRAS, NRAS, BRAF, PIK3CA, and FBXW7 mutations was 47.2%, 1.9%, 1.9%, 12%, and 14.8%, respectively. KRAS mutation codon 12, 13, 59, 61, 117, and 146 mutations were identified in 29.6%, 8.3%, 1.8%, 0.9%, 0.0%, and 8.3%, respectively. KRAS Exon 4 had better DFS compared with Exon 2 and 3. Conclusions: This study is the first to comprehensively report hotspot mutations using NGS in Thai colon cancer patients. The most commonly identified gene mutation frequencies among Thai patients (KRAS, NRAS, BRAF, TP53, and PIK3CA) were similar to the gene mutation frequencies reported in Western population, except for subgroup of KRAS codon 146 and FBXW7 mutations that had a slightly higher frequency.

Background: Non-squamous cell carcinoma of the head and neck (HNnSCCA) is a rare tumor. Surgery is the standard treatment for resectable non-metastatic patients. Post-operative radiation (RT) is indicated for high-risk patients. No data from the randomized controlled trial utilizing post-operative concurrent chemoradiation (CCRT) is available. This study was aimed to determine the benefit of post-operative CCRT in the patients with resectable non-metastatic HNnSCCA. Methods: We retrospectively reviewed data of 139 patients with HNnSCCA (excluding nasopharyngeal, neuroendocrine, and skin cancers) who underwent surgery and post-operative radiation (RT) at Siriraj Hospital from 2009–2015. Results: Ninety-nine of the 139 patients had RT alone and 40 had CCRT. More patients receiving CCRT had ≥ one high-risk feature (80% CCRT vs. 57.6% RT; p=0.018). Five-year disease-free survival (DFS) and overall survival (OS) did not differ between the groups (58.6% CCRT vs. 68.2% RT; p=0.35 and 81.7% CCRT vs. 81.0% RT; p=0.35, respectively). Interestingly, post-operative CCRT was independently associated with significantly superior DFS (hazard ratio, HR 0.29; 95% confidence interval, CI 0.10 to 0.86; p=0.02) and OS (HR 0.08; 95% CI 0.01 to 0.43; p=0.003) according to multivariable analyses. Conclusion: Post-operative CCRT was associated with better survival in high-risk patients with resectable non-metastatic HNnSCCA comparing with post-operative RT alone. Post-operative CCRT might be considered as a treatment option for these patients.

Background: RSK4 is a member of the p90 Ribosomal S6 kinase family that promotes metastasis and chemoresistance in non-small cell lung cancer and its inhibition improves therapeutic outcome in in vivo and ex vivo models. Here, we show that RSK4 inhibition activates HIF-1alpha and also impacts glucose and glutamine metabolism in lung adenocarcinoma cells. Methods: RSK4 was downregulated in lung adenocarcinoma cells by RNA interference or CRISPR/Cas9 technology. Glycolytic rate assay and mitochondrial stress test were performed using the Seahorse XFe96 analyzer. ATP levels were determined by the CellTiter Glo assay. Intracellular metabolites were profiled by untargeted mass spectrometry and U-13C glutamine labelling. 3D spheroids viability was assessed by CellTiter Glo 3D assay with or without glycolysis inhibition using 2-deoxy-D-glucose (2DG) or glutaminase inhibition using 6-Diazo-5-oxo-L-norleucine (DON). Protein expression was determined by Western blotting. Results: RSK4 downregulation enhanced glycolysis, oxidative phosphorylation, and ATP production in A549 cells. The RSK4-silenced cells showed increased lactate production and glutamine consumption via reductive carboxylation. This sensitized RSK4-silenced cells to 2DG and DON treatments. Mechanistically, RSK4 knockdown upregulates HIF-1alpha in normoxia through decreased activation of PHD2, an enzymes that targets HIF-1alpha for degradation. Stabilization of HIF-1alpha resulted in increased transcription of HK2, the rate limiting enzyme of glycolysis, and GLS1, which hydrolyzes glutamine. Conclusion: RSK4 knockdown promotes a pseudo-hypoxic phenotype in lung adenocarcinoma cells characterized by increased glycolysis and enhanced glutamine utilization via reductive carboxylation. Targeting these changes potentiates the effects of RSK4 inhibition and may represent new therapeutic opportunities for this tumor type. Citation Format: Lucksamon Thamlikitkul, Peng Chai, Cristina Balcells Nadal, Rajat Roy, Xiao-Ming Sun, Marion MacFarlane, Hector Keun, Michael Seckl, Olivier Pardo. RSK4 inhibition promotes pseudo-hypoxic metabolic responses in lung adenocarcinoma [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 3037.

The purpose of this study is to determine the efficacy of ginger for reducing chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients receiving adriamycin and cyclophosphamide (AC) regimens. We enrolled breast cancer patients receiving AC who experienced moderate to severe nausea or vomiting during the first chemotherapy cycle. Subjects were randomized to receive a 500-mg ginger capsule or placebo twice a day for 5 days starting on the first day of the second AC cycle and were switched to the other treatment in the third cycle. All participants also received ondansetron and dexamethasone for CINV prophylaxis. Nausea severity was recorded once a day during the first 5 days of each cycle. The primary outcome was reduction in nausea score. Thirty-four subjects (68 cycles of AC) were enrolled. Mean (range) maximum nausea score in the first AC cycle was 58 (40–90). Thirty-three subjects (97 %) received the same AC doses in the second as in the third cycle. Mean (±standard error) maximum nausea scores in patients receiving ginger and placebo were 35.36 (±4.43) and 32.17 (±3.71), respectively. The difference in mean maximum nausea scores was 3 (95 % confidence interval, −3 to 9; P = 0.3). There were no significant differences between ginger and placebo in terms of vomiting incidence and severity, rescue medication use, chemotherapy compliance, and adverse events. Ginger (500 mg) twice daily was safe, but conferred no additional benefit in terms of reducing nausea severity in breast cancer patients receiving AC and ondansetron and dexamethasone for CINV prophylaxis.

e17582 Background: Surgery is the mainstay of treatment for resectable non-metastatic NSCCA of head and neck. Postoperative radiation (RT) is delivered to patients (pt) with high risk for recurrence. Unlike the squamous cell counterpart where survival advantage from adding chemotherapy (CMT) as a radio-sensitizer is evident, the benefit of CCRT is uncertain in NSCCA pt. We hypothesized that CCRT would improve disease free survival (DFS), comparing to RT alone. Methods: NSCCA of head and neck pt who underwent curative surgery and RT at Siriraj hospital from 2006 to 2015 were included in this retrospective study. Patients with residual tumor after surgery or neuroendocrine histology were excluded. The primary outcome was DFS. The secondary outcome was overall survival (OS). Results: We included 139 pt, 99 (71.2%) had RT while 40 (28.8%) had CCRT. Baseline characteristics, including age, gender, primary site, histology and radiation dose were similar between 2 groups. Salivary gland was the most common primary site (67.6%). The most common histology was adenoid cystic carcinoma (35.3%), followed by mucoepidermoid carcinoma (25.9%). Patients who received RT alone had earlier stage (Stage I 29.3%, Stage IVa 14.1%), compared to CCRT group (Stage I 7.7%, Stage IVa 38.5%), p = 0.003. High risk features (positive margin, extranodal extension or ≥ 2 cervical lymph nodes metastasis) were found in 42% and 62% of pt with RT and CCRT, respectively (p = 0.03). In CCRT group, 92% of pt received cisplatin every 3 weeks during RT period. With the median follow-up time of 54.9 months, 3-year DFS was 79.4% and 79.5% in RT and CCRT groups, respectively (p = 0.22). There was no significant difference in 3-year OS between RT and CCRT groups (89.2% vs 89.9%, p = 0.76). Among pt with high-risk features (n = 67, 48.2%), 3-year DFS and OS were not significantly different between treatment groups. However, among pt without high-risk features, 3-year DFS in RT group was significantly higher than CCRT group (84.8% vs 79.0%, p = 0.04). Conclusions: This study demonstrates no survival benefit from adding concurrent CMT to RT following curative surgery in NSCCA of head and neck. Moreover, addition of CMT may be detrimental in pt without high-risk features.