FAK-JAK 2 dual Inhib

However, clinical studies of single agent MEKi or combinations with docetaxel in mutant KRAS NSCLC patients were associated with low response rates...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 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.

Therapeutic targeting of KRAS has proven challenging until recent success of KRAS-G12C inhibitor AMG510 that demonstrated tumor regression in lung and colon cancer patients with a KRAS-G12C mutation. Additional combination data in KRAS-G12C mutant cancer models will be presented. Overall, these studies warrant further clinical investigation on the combination of KRAS-G12C inhibitors with repotrectinib in patients with KRAS-G12C mutation for potential response and duration improvement of current investigational KRAS-G12C inhibitors.

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. 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.