Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer

Abstract

// C. Allison Stewart 1 , Pan Tong 2 , Robert J. Cardnell 1 , Triparna Sen 1 , Lerong Li 2 , Carl M. Gay 1 , Fatemah Masrorpour 1 , You Fan 1 , Rasha O. Bara 1 , Ying Feng 3 , Yuanbin Ru 3 , Junya Fujimoto 4 , Samrat T. Kundu 1 , Leonard E. Post 3 , Karen Yu 3 , Yuqiao Shen 3 , Bonnie S. Glisson 1 , Ignacio Wistuba 4 , John V. Heymach 1 , Don L. Gibbons 1 , Jing Wang 2 and Lauren Averett Byers 1 1 Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 3 BioMarin Pharmaceutical, San Rafael, CA 94901, USA 4 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Correspondence to: Lauren Averett Byers, email: lbyers@mdanderson.org Keywords: SCLC, SLFN11, ATM, EMT, PARP inhibitor Received: December 10, 2016      Accepted: January 19, 2017      Published: February 15, 2017 ABSTRACT Small cell lung cancer (SCLC) is one of the most aggressive forms of cancer, with a 5-year survival <7%. A major barrier to progress is the absence of predictive biomarkers for chemotherapy and novel targeted agents such as PARP inhibitors. Using a high-throughput, integrated proteomic, transcriptomic, and genomic analysis of SCLC patient-derived xenografts (PDXs) and profiled cell lines, we identified biomarkers of drug sensitivity and determined their prevalence in patient tumors. In contrast to breast and ovarian cancer, PARP inhibitor response was not associated with mutations in homologous recombination (HR) genes (e.g., BRCA1/2 ) or HRD scores. Instead, we found several proteomic markers that predicted PDX response, including high levels of SLFN11 and E-cadherin and low ATM. SLFN11 and E-cadherin were also significantly associated with in vitro sensitivity to cisplatin and topoisomerase1/2 inhibitors (all commonly used in SCLC). Treatment with cisplatin or PARP inhibitors downregulated SLFN11 and E-cadherin, possibly explaining the rapid development of therapeutic resistance in SCLC. Supporting their functional role, silencing SLFN11 reduced in vitro sensitivity and drug-induced DNA damage; whereas ATM knockdown or pharmacologic inhibition enhanced sensitivity. Notably, SCLC with mesenchymal phenotypes (i.e., loss of E-cadherin and high epithelial-to-mesenchymal transition (EMT) signature scores) displayed striking alterations in expression of miR200 family and key SCLC genes (e.g., NEUROD1, ASCL1, ALDH1A1, MYCL1 ). Thus, SLFN11, EMT, and ATM mediate therapeutic response in SCLC and warrant further clinical investigation as predictive biomarkers.