Abstract 297: Epigenetic activation of IGF1R signaling promotes resistance to momelotinib and MEK inhibition in KRAS-driven lung cancer

KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), yet remains resistant to targeted therapy. Previously, we reported that RAL-TBK1 activation downstream of KRAS promotes an autocrine cytokine circuit that fuels tumorigenesis. Interruption of this signaling by treatment with momelotinib, an inhibitor of TBK1/IKKe and JAK kinases, together with MEK inhibition, was effective in the aggressive Kras-p53 (KP) mouse lung cancer model. These findings have prompted a human clinical trial of momelotinib and trametinib in advanced refractory KRAS mutant NSCLC. Because this combination leads to acquired resistance in mice, we sought to understand additional pathways that could compensate for TBK1/JAK and MEK inhibition. Receptor tyrosine kinase (RTK) profiling of A549 cells treated with momelotinib revealed delayed activation of IGF1 receptor (IGF1R) signaling. Indeed, IGF1 supplementation partially rescued momelotinib-induced growth arrest of A549 cells, while combination of momelotinib with the dual IGF1R/insulin receptor (IR) inhibitor linsitinib cooperated to impair cell viability, which was more pronounced in KRAS/STK11 (encoding LKB1) mutant cell lines compared with LKB1 wild type cell lines. Triple momelotinib/trametinib/linsitinib therapy also improved tumor shrinkage in Kras-Lkb1 (KL) mice compared with KP mice. However, chronic treatment with this triple combination required pulse therapy due to toxicity, and was inferior to momelotinib/trametinib dosed daily, which itself promoted deep responses in KL mice lasting 6 weeks. In parallel, we analyzed mediators of acquired resistance to chronic momelotinib and MEK inhibitor exposure in A549 cells. Interestingly, IGF1 expression was dramatically upregulated in resistant cells, in contrast to IGF2, and enhanced autocrine activation of IGF1R signaling. Importantly, both IGF1 upregulation and inhibitor resistance were completely reversible after drug withdrawal for several passages, yet reappeared quickly upon drug readdition, suggesting epigenetic reprogramming. Consistent with this hypothesis, whereas global H3K27 histone acetylation was decreased in resistant cells, this epigenetic mark was strongly enriched at the IGF1 promoter and linked tightly with both IGF1 levels and drug resistance. Treatment of resistant A549 cells with the BRD4 inhibitor JQ1 completely suppressed IGF1 expression and downstream IGF1R activation, and impaired cell viability. Combination JQ1 treatment also prevented momelotinib/MEK inhibitor induction of IGF1 in A549 cells, synergized to reduce outgrowth of resistant cells, and was well tolerated as daily triple combination therapy in mice. Together, these findings suggest the potential of BET inhibition to synergize with and prevent the development of acquired resistance to momelotinib and MEK inhibitor treatment in KRAS mutant NSCLC. Citation Format: Shunsuke Kitajima, Hajime Asahina, Jillian D. Cavanaugh, Ting Chen, Ashley A. Merlino, Thai C. Tran, Kwonk-Kin Wong, David A. Barbie. Epigenetic activation of IGF1R signaling promotes resistance to momelotinib and MEK inhibition in KRAS-driven lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 297.