MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

Marcel A Dammert,Lauren A Byers,John T Poirier,Stefanie Böhm,Reinhard Büttner,Luka Ozretić,Johannes Brägelmann,Hannah L Tumbrink,Triparna Sen,Sebastian Klein,Carina Lorenz,Roman K Thomas,Elmar Wolf,Niloufar Monhasery,Anna Schmitt,Annika Marx,Jeremy Ryan,Abbie S Ireland,Roberta Castiglione,Christopher P Whitney,Hans Christian Reinhardt ,Ron D Jachimowicz,Milind D Chalishazar,Rachelle R Olsen,Trudy G Oliver,Matthew R Guthrie,Anthony Letaï ,Martin L Sos

doi:10.1038/s41467-019-11371-x

Abstract

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.

Highlights

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets
MYC paralogs on overall survival remains unclear due to the limited amount of available expression data in SCLC patient cohorts (Supplementary Fig. 1a)[12]
These observations prompted us to dissect the specific role of each MYC paralog in SCLC, with the CRISPR/dCas[9] Synergistic Activation Mediator (SAM) CRISPR activation (CRISPRa) system[13] that allows efficient induction of endogenous gene expression

Summary

Introduction

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients. Using CRISPR/dCas9-mediated MYC paralog activation, we uncover a link between MYC signaling and the regulation of the apoptotic machinery with direct implications for the selection of targeted drugs for SCLC patients. Myc activation suppressed Bcl[2] expression in CRISPRa cells (p = 0.004 mock vs Myc, two-tailed unpaired t test) (Fig. 1i) This anti-correlation between MYC and BCL2 appears to be an exception rather than the rule since we primarily found a positive correlation between MYC and BCL2 expression in the pan-cancer CCLE cohort[16,17] (Supplementary Fig. 1l). MYC paralog expression is tightly linked with BCL2 expression, which determines susceptibility to cell cycle checkpoint inhibitors

Methods

Results

Conclusion