Abstract 4187: Loss of SLFN11 or Gain of TWIST1 Promote Chemotherapy Resistance in Small Cell Lung Cancer

Abstract The majority of patients with small cell lung cancer (SCLC) who are treated with first-line platinum/etoposide chemotherapy develop therapeutic resistance, but little is mechanistically understood how resistance develops in patients. This is partly due to limited access to historic paired tissue samples, few investigational re-biopsy programs and the aggressive nature of this disease. In this study we used a collection of 10 treatment-naïve, patient-derived xenograft (PDX) models of SCLC to determine how resistance to chemotherapy can be acquired in vivo, by cycling weekly cisplatin and etoposide, followed by serial passaging of tumor cells capable of surviving and proliferating through treatment. Applying whole transcriptome (RNAseq), exome and high-depth targeted sequencing approaches to paired parental and resistant populations revealed minimal recurrent mutations; however, two consistent gene expression changes were observed, implicating either a decrease in SLFN11 or an increase in TWIST1 transcript levels may promote resistance. We validated both mechanisms in vitro using conditional gain and loss of function experiments in SCLC cell lines of human and mouse origin. Where suppression of SLFN11 was associated with resistance to select classes of DNA damaging agents, gaining TWIST1 produced a broad resistance phenotype, consistent with an epithelial-to-mesenchymal transition. Increased sensitivity to chemotherapy through overexpression of SLFN11 was observed only in cell lines with low levels of TWIST1. Importantly, TWIST1 knockdown or knockout did not dramatically change the sensitivity to chemotherapy in multiple TWIST1-high cell lines tested, suggesting that directly targeting TWIST1 may be of limited utility in SCLC. We extended these results by modeling acquired resistance to cisplatin and etoposide in a triple knockout (p53/Rb/p130) mouse allograft model of SCLC, finding that increased expression of TWIST1 was associated with chemotherapy resistance, but did not confer a greater metastatic potential in a tumor type with an already high predilection for metastasis. Understanding the relative expression of SLFN11 and TWIST1 at baseline and upon clinical relapse may be informative in determining therapeutic options for SCLC patients that no longer respond to platinum and etoposide. Citation Format: Eric E. Gardner, Benjamin H. Lok, Valentina E. Schneeberger, Elisa de Stanchina, John T. Poirier, Charles M. Rudin. Loss of SLFN11 or gain of TWIST1 promote chemotherapy resistance in small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4187.