Repotrectinib Increases Effectiveness Of Mek Inhibitor Trametinib In Kras Mutant Cancer Models Via Simultaneous Src/Fak/Jak2 Inhibition

Kirsten Rat Sarcoma Viral Oncogene homolog (KRAS) is the most frequently mutated oncogene in a broad spectrum of human cancers, including ~30% of non-small cell lung cancer (NSCLC), ~45% of colorectal cancer (CRC) and ~75% of pancreatic cancer. The MEK inhibitor trametinib, which targets the primary downstream signaling pathway activated by mutant KRAS, has shown limited activity when used as a single agent in patients with previously treated KRAS-mutant positive NSCLC. Compensatory upregulation of the PI3K/AKT survival signaling and intrinsic or treatment induced epithelial-to-mesenchymal transition (EMT) are among resistance mechanisms of MEK inhibition in KRAS mutant cancers. SRC/FAK signaling modulates the PI3K/AKT survival pathway and is involved in the integrin mediated EMT signaling. In addition, MEK inhibition has been reported to activate the JAK2/STAT3 pathway to evade therapy. Therefore, the combination of a MEK inhibitor with agents that simultaneously inhibit SRC, FAK and JAK2 may represent a promising therapeutic approach to effectively target KRAS mutant cancers. Repotrectinib, a next generation ROS1/TRK/ALK investigational drug, also inhibits SRC/FAK/JAK2 at therapeutically relevant concentrations. Here, we present synergistic effects of repotrectinib in combination with trametinib in KRAS mutant cancer models. Increased anti-proliferative activity was demonstrated by the combination across panels of KRAS mutant NSCLC and CRC cell lines that harbor a spectrum of KRAS mutations. Additionally, the combination of trametinib and repotrectinib in KRAS mutant cell lines caused an enhanced induction of apoptosis in comparison with trametinib or repotrectinib alone. Trametinib induced a rebound in phospho-AKT (pAKT) levels in a subset of KRAS mutant cells which was substantially suppressed by the combination with repotrectinib. In contrast, suppression of the trametinib-induced pAKT rebound was not achieved by combinations of trametinib with dasatinib (SRCi), ruxolitinib (JAK1/2i), or defactinib (FAKi), suggesting that concomitant SRC/FAK/JAK2 inhibition is potentially necessary. Combination of trametinib and repotrectinib in KRAS mutant murine xenograft studies resulted in suppression of SRC/FAK/STAT3/EGFR/ERK phosphorylation and the enhancement of tumor apoptosis. Importantly, the combination of repotrectinib and trametinib demonstrated increased in vivo anti-tumor effect compared to trametinib alone. Our data suggest that the combination of repotrectinib with trametinib may sustainably suppress the mutant KRAS network signaling to achieve more potent and durable anti-tumor efficacy, and that further clinical investigation of the combination treatment of a MEK inhibitor with repotrectinib in patients with KRAS mutant cancers is warranted. Citation Format: Brion Murray, Wei Deng, Dayong Zhai, Laura Rodon, Nathan Lee, J. Jean Cui. Repotrectinib increases effectiveness of MEK inhibitor trametinib in KRAS mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1957.