Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS.

Cancer Cell
Authors
Keywords
Abstract

Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic.

Year of Publication
2018
Journal
Cancer Cell
Volume
34
Issue
3
Pages
439-452.e6
Date Published
2018 09 10
ISSN
1878-3686
DOI
10.1016/j.ccell.2018.08.009
PubMed ID
30205046
PubMed Central ID
PMC6422029
Links
Grant list
R01 CA216188 / CA / NCI NIH HHS / United States
R01 CA122794 / CA / NCI NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
U01 CA233084 / CA / NCI NIH HHS / United States
R01 CA163896 / CA / NCI NIH HHS / United States
R01 CA166480 / CA / NCI NIH HHS / United States
R01 CA140594 / CA / NCI NIH HHS / United States
R01 CA190394 / CA / NCI NIH HHS / United States
R01 CA205150 / CA / NCI NIH HHS / United States
U01 CA217885 / CA / NCI NIH HHS / United States