Protein Kinase Signaling in Cisplatin-Resistant ASCL1-High SCLC
Abstract
Research: Small cell lung cancer (SCLC) which accounts for around 15% of lung cancer cases is the most aggressive subtype of lung cancer with a 5-year survival rate of less than 5%. The results of numerous clinical trials have been disappointing and to date no approved targeted-therapy for SCLC is available. Due to very limited improvements in SCLC therapy or survival over the past 30 years, SCLC has been categorized as a recalcitrant cancer. The immunotherapy drug atezolizumab has recently received approval for being used together with chemotherapy. Compared with chemotherapy along, however, adding atezolizumab only extends patient median overall and progression-free survival by two and one month, respectively. The lack of targeted therapy for SCLC stands in sharp contrast with the remarkable progress being made in treating subtypes of lung adenocarcinoma. By targeting tumor specific oncogenic mutations or translocations, ever-increasing personalized therapeutic approaches are available to lung adenocarcinoma patients. SCLC, however, is clinically managed as a single disease entity with no attempt to stratify patient groups that might be most amenable to a particular treatment. Platinum-based standard treatment (e.g., cisplatin) usually leads to robust initial clinical response, but the majority of patients quickly succumb to chemoresistant recurrence, the mechanism of which remains largely unclear. Therefore, identification of critical factors responsible for the emergence of chemoresistance will not provide personalized treatment and also help identify cancer patients who may or may not benefit platinum-based chemotherapies. In order to discover how small cell lung cancer become resistant to platinum, we initiate a screening campaign, aimed to identify critical factors in cancer cell that can confer platinum resistance. Our screening assay identified protein kinase MAST1 as a potential critical factor conferring platinum resistance in small cell lung cancer. Inhibition of MAST1 sensitized small cell lung cancer cells to platinum treatment. Importantly, analysis of publicly available cancer database shows MAST1 level is elevated in ASCL1-high small cell lung cancer, a major subtype of SCLC. MAST1 abundance correlates with platinum resistance in SCLC cell lines and patient tumors. Our study further revealed that MAST1 directly activates PLK1 to promote cell survival in the presence of platinum. Based on these preliminary findings, we hypothesize that MAST1 promotes platinum resistance in ASCL1-high small cell lung cancer through its downstream effector PLK1. This proposal will be the first to rigorously characterize the role of MAST1-PLK1 signaling in driving platinum resistance and validate MAST1 as a therapeutic target to overcome platinum resistance in ASCL1-high SCLC. Completion of the proposed studies will obtain a comprehensive picture of how SCLC cells survive under platinum pressure using MAST1-PLK1 as a key factor, which is consistent with the LCRP Area of Emphasis: understand mechanisms of resistance to treatment (primary and secondary). Instead of screening for new compounds targeting MAST1 that may take years to reach clinical setting, we deployed a “drug repurposing” strategy and identified a clinical trial-staged small molecule kinase inhibitor as a potent MAST1 inhibitor with promising capability of cisplatin sensitization. This strategy aims to provide effective platinum-based regimens to SCLC patients in the immediate future. Also, we will validate MAST1-PLK1 as biomarkers predictive of cisplatin/anti-MAST1 response in ASCL1-high SCLC, which would enable rapid screening and be useful in selecting patients for future human trials. This is also in line with the LCRP Area of Emphasis: understand predictive markers to identify responders and nonresponders. The present goal is to take the first critical steps bridging this new discovery to longer-term work elucidating the molecular
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010309
Entities
People
- Lingtao Jin
Organizations
- United States Army
- University of Florida