Investigating Drivers of Chemoresistance in Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by rapid emergence of chemoresistant disease. To study the role of MYC family members in SCLC chemoresistance we utilized genetically engineered mouse models of SCLC and found that MYCN and MYCL overexpression abrogated response to cisplatin-etoposide chemotherapy. We extended these data to genetically perturb chemosensitive patient derived xenograft (PDX) models of SCLC. In chemosensitive PDX models, overexpression of either MYCN or MYCL also conferred a switch to chemoresistance. To investigate therapeutic strategies for MYCN-overexpressing SCLC, we utilized a genome-scale CRISPR-Cas9 sgRNA screen and identified the deubiquitinase USP7 as a MYCN-associated synthetic vulnerability. Pharmacological inhibition of USP7 re-sensitized chemoresistant MYCN-overexpressing PDX models to chemotherapy in vivo. Our findings show that MYC family member overexpression drives SCLC chemoresistance and provide a therapeutic strategy to restore chemosensitivity. To further investigate drivers of SCLC chemoresistance beyond MYC family members we designed and built a small, focused sgRNA library targeting key genes of interest in SCLC. Using chemosensitive PDX models, we performed in vivo CRISPR-Cas9 sgRNA screens both on a genome-wide scale and on a smaller scale using our focused library. These screens identified several candidate genes and pathways, most notably the SAGA complex, for validation as potential drivers of chemoresistance in SCLC.