ausblenden:
Schlagwörter:
Animals
Antineoplastic Agents/pharmacology/therapeutic use
Apoptosis/drug effects/*genetics
CRISPR-Cas Systems/genetics
Cell Line, Tumor
DNA Damage/drug effects/genetics
Disease Models, Animal
Gene Expression Regulation, Neoplastic/drug effects/*genetics
HEK293 Cells
Humans
Lung Neoplasms/drug therapy/*genetics
Mice
Molecular Targeted Therapy/methods
Proto-Oncogene Proteins c-myc/genetics/*metabolism
RNA, Small Interfering/metabolism
Small Cell Lung Carcinoma/drug therapy/*genetics
Zusammenfassung:
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.
