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

Nature Communications
Marcel A DammertMartin L Sos

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.

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Citations

Feb 19, 2020·Expert Opinion on Therapeutic Targets·Jane S Y SuiSteven G Gray
Dec 19, 2019·Frontiers in Immunology·Giuseppe ErcolanoCamilla Jandus
Feb 20, 2020·Nature Reviews. Molecular Cell Biology·Apoorva BaluapuriMartin Eilers
Dec 10, 2020·EMBO Molecular Medicine·Julie KoJulien Sage
Jan 11, 2021·Trends in Pharmacological Sciences·Dexter Kai Hao ThngEdward Kai-Hua Chow
Feb 6, 2020·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·John T PoirierTrudy G Oliver
Feb 23, 2021·Frontiers in Oncology·Ruochen LiuHongjuan Cui
Apr 8, 2021·Nature Communications·Christina M BebberSilvia von Karstedt
Sep 12, 2021·Nature Reviews. Clinical Oncology·Renumathy DhanasekaranDean W Felsher

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Datasets Mentioned

BETA
E-MTAB-7412
E-MTAB-7411

Methods Mentioned

BETA
xenograft
immunoprecipitation
PCR
ChIP
transfection
exome sequencing
RNA-seq
RNAseq
co-immunoprecipitation
electrophoresis

Clinical Trials Mentioned

NCT03216343
NCT03092934
NCT02719691
NCT02134067
NCT01118611
NCT02735980
NCT02797964
NCT02797977
NCT02873975
NCT02038647

Software Mentioned

Trace
Prism
R package synergyfinder
Draw
Sclust
STAR
MEM
GraphPad Prism
QUMA
Image Algebra

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