Abstract 1104: Repotrectinib increases effectiveness of MEK inhibitors in KRAS mutant cancer models

Abstract

KRAS is the most frequently mutated oncogene in cancers, accounting for approximately 25% of non small cell lung cancer (NSCLC), 45% of colorectal cancer (CRC), and 75% of pancreatic cancer. KRAS G12D and G12V mutations account for a large percent of mutant KRAS cancers (36% of NSCLC; 57% of CRC; 71% of pancreatic). MEK1/2 are critical downstream effectors of KRAS signaling and preclinical studies in KRAS mutant models show sensitivity to MEK inhibitors (MEKi). However, clinical studies of single agent MEKi or combinations with docetaxel in mutant KRAS NSCLC patients were associated with low response rates. Preclinical studies show that effectiveness of MEK inhibition can be limited by multiple resistance mechanisms such as compensatory upregulation of PI3K/AKT via SRC/FAK signaling, or activation of the JAK2/STAT3 pathway. Repotrectinib is a next-generation ROS1/TRK inhibitor with SRC/FAK/JAK2 inhibitory potencies which may suppress adaptive resistance to MEK inhibitors. In the current study, repotrectinib combinations with KRAS signaling network inhibitors including MEK (trametinib, selumetinib), MEK/RAF (VS-6766), ERK (LY3214996), SHP2 (TNO155) were explored. Repotrectinib/trametinib and repotrectinib/VS-6766 combinations yielded significant effects on cancer cell viability in NSCLC and pancreatic patient-derived spheroid models harboring KRASG12D and KRASG12V mutations. The repotrectinib/trametinib combination in A427 cells (NSCLC KRASG12D) exhibited increased inhibition of pAKT and pS6 compared to single agent treatments. This coincided with greater upregulation of p27 and elevated PARP cleavage, resulting in enhanced induction of apopotosis. To assess acquired MEKi resistance, several KRAS mutant cancer models were cultured under trametinib selection. Evaluation of trametinib-resistant cancer cells revealed activation of STAT3, FAK, and AKT signaling along with elevated S6 protein phosphorylation, which could be suppressed and resensitized to trametinib by combining with repotrectinib. Repotrectinib/trametinib combination in a syngeneic GEMM KRASG12D lung model had greater tumor growth inhibition than either single agent treatment. A similar combination efficacy benefit was observed in a HCT116 (CRC KRASG13D) xenograft model concomitant with suppression of SRC/FAK/STAT3/ERK activation. Taken together, repotrectinib combinations with MEK inhibitors demonstrated enhanced efficacy in both in vitro and in vivo preclinical models. Repotrectinib was shown to suppress molecular mechanisms of adaptive resistance mechanisms to MEK inhibition in preclinical models. These results suggest that the combination of repotrectinib with MEKi can repress the mutant KRAS signaling network to achieve more potent and durable anti-tumor activity and warrants clinical investigation in patients with KRASG12D and KRASG12V mutant cancers. Citation Format: Nathan V. Lee, Wei Deng, Dayong Zhai, Laura Rodon, Ana Parra, Jessica Cowell, Afsheen Banisadr, Xin Zhang, Brion W. Murray. Repotrectinib increases effectiveness of MEK inhibitors in KRAS mutant cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1104.

KRAS Mutations in Squamous Cell Carcinomas of the Lung

“…The farnesyltransferase inhibitor tipifarnib received breakthrough therapy designation from the FDA for HRAS -mutated head and neck SCC ( 16 ). Furthermore, combined inhibition of multiple pathways of the KRAS signaling network may provide clinical benefit in patients with KRAS p.G12D-mutated tumors, as shown by preclinical data of the MEK inhibitor trametinib in combination with the ROS1/TRK and SRC/FAK/JAK2 inhibitor repotrectinib ( 17 ).…”