MEKi-based combination strategies for targeting KRAS-driven cancer

Background: KRAS is one of the most frequently mutated oncogenes in human cancer. Recent successes with G12C-specific inhibitors are changing treatment paradigm this subset cancer patients. An alternative strategy targeting downstream effectors, such as MEK. However, MEK have historically proven unsuccessful monotherapy mutant cancers, highlighting need for combinatory approaches. One possibility combination and SOS1 inhibition, which may overcome adaptive resistance to MEKi by blocking SOS1-mediated reactivation MAPK signaling. Another promising approach combine Bromodomain extra-terminal (BET) proteins. While BET exhibit broad anti-tumor activity preclinical models, BETi demonstrated only moderate clinical activity. Resistance has been, at least partially, attributed pathway upregulation, suggesting that a help resistance. Material Methods: Here, we present BI 3011441, potent selective inhibitor MEK1/2. Using vitro assays, compare 3011441 other stage inhibitors. We also 1701963 894999 - two potent, selective, orally bioavailable BET, respectively. Both combinations tested and/or vivo across panel pancreatic ductal adenocarcinoma (PDAC), colorectal (CRC) non-small cell lung (NSCLC) models. Results: efficiently inhibits ERK phosphorylation cell-based assays demonstrates strongest growth inhibition BRAF or lines among tested. In vivo, leads dose-dependent modulation pathway, translates into xenograft models KRAS-driven The SOS1i synergistically decreases signaling resulting enhanced efficacy including NSCLC, CRC PDAC. NSCLC results 10% partial responses (PR) 70% stable disease (SD) defined modified Response Evaluation Criteria Solid Tumors (mRECIST). PDAC 30% 43% SD, When combined clinically relevant concentrations 894999, strongly proliferation induces apoptosis cells. Synergy observed 17 out 44 different indications harboring mutations. Conclusions: summary, show combining lead improved tumors, likely circumventing pathway-related Conflict interest: Other Substantive Relationships: authors either employees financial relationships Boehringer Ingelheim.