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

Cancer cell (2020-04-04)
Stephanie L Guerra, Ophélia Maertens, Ryan Kuzmickas, Thomas De Raedt, Richard O Adeyemi, Caroline J Guild, Shawna Guillemette, Amanda J Redig, Emily S Chambers, Man Xu, Hong Tiv, Sandro Santagata, Pasi A Jänne, Stephen J Elledge, Karen Cichowski
ABSTRACT

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.

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Sigma-Aldrich
(2-Hydroxypropyl)-β-cyclodextrin, powder, BioReagent, suitable for cell culture