Research ArticleCancer

Application of a MYC degradation screen identifies sensitivity to CDK9 inhibitors in KRAS-mutant pancreatic cancer

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Science Signaling  16 Jul 2019:
Vol. 12, Issue 590, eaav7259
DOI: 10.1126/scisignal.aav7259

Screening tumor vulnerability

Mutations in the gene encoding the guanosine triphosphatase KRAS are common drivers of various cancers. Because most mutant KRAS proteins are currently too difficult to therapeutically target, alternative targets in KRAS-mutant tumors must be identified. Given a previous observation that KRAS-mutant pancreatic cancers (PDACs) rely on the transcription factor MYC, Blake et al. screened for inhibitors that decreased MYC protein abundance. They found that an inhibitor of the cell cycle–associated kinase CDK9 decreased MYC abundance at both the mRNA and protein levels in a manner independent of KRAS signaling itself. This finding reveals a potential therapeutic target for patients with KRAS-mutant PDAC and possibly also those with more generally MYC-dependent cancers.

Abstract

Stabilization of the MYC oncoprotein by KRAS signaling critically promotes the growth of pancreatic ductal adenocarcinoma (PDAC). Thus, understanding how MYC protein stability is regulated may lead to effective therapies. Here, we used a previously developed, flow cytometry–based assay that screened a library of >800 protein kinase inhibitors and identified compounds that promoted either the stability or degradation of MYC in a KRAS-mutant PDAC cell line. We validated compounds that stabilized or destabilized MYC and then focused on one compound, UNC10112785, that induced the substantial loss of MYC protein in both two-dimensional (2D) and 3D cell cultures. We determined that this compound is a potent CDK9 inhibitor with a previously uncharacterized scaffold, caused MYC loss through both transcriptional and posttranslational mechanisms, and suppresses PDAC anchorage-dependent and anchorage-independent growth. We discovered that CDK9 enhanced MYC protein stability through a previously unknown, KRAS-independent mechanism involving direct phosphorylation of MYC at Ser62. Our study thus not only identifies a potential therapeutic target for patients with KRAS-mutant PDAC but also presents the application of a screening strategy that can be more broadly adapted to identify regulators of protein stability.

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