A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers.

While KRAS mutations are common in non-small cell lung cancer (NSCLC), effective treatments are lacking. Here, we report that half of KRAS-mutant NSCLCs aberrantly express the homeobox protein HOXC10, largely due to unappreciated defects in PRC2, which confers sensitivity to combined BET/MEK inhibitors in xenograft and PDX models. Efficacy of the combination is dependent on suppression of HOXC10 by BET inhibitors. We further show that HOXC10 regulates the expression of pre-replication complex (pre-RC) proteins in sensitive tumors. Accordingly, BET/MEK inhibitors suppress pre-RC proteins in cycling cells, triggering stalled replication, DNA damage, and death. These studies reveal a promising therapeutic strategy for KRAS-mutant NSCLCs, identify a predictive biomarker of response, and define a subset of NSCLCs with a targetable epigenetic vulnerability.
Competing Interests: Declaration of Interests P.A.J. consults for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, and Mirati Therapeutics; has sponsored research agreements with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Astellas Pharmaceuticals, and Revolution Medicines. S.J.E. is a founder of TSCAN Therapeutics, MAZE Therapeutics, and Mirimus and is on the SAB of CRISPR Therapeutics, Homology Medicine, TSCAN Therapeutics, XChem, and advises for MPM. None of these represent competing interests.
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