SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status

KRAS is the most commonly mutated oncogene; targeted therapies have been developed against mediators of key downstream signaling pathways, predominantly components of the RAF/MEK/ERK kinase cascade. Unfortunately, single-agent efficacy of these agents is limited both by intrinsic and acquired resistance. Survival of drug-tolerant persister cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) and drive therapeutic resistance. Here, we show that targeting the key RTK/RAS pathway signaling intermediates SOS1 or KSR1 both enhances the efficacy of and prevents resistance to the MEK inhibitor trametinib in KRAS-mutated lung and colorectal adenocarcinoma cell lines depending on the specific mutational landscape. The SOS1 inhibitor BI-3406 enhanced the efficacy of trametinib and prevented trametinib resistance by targeting TICs, but only in KRASG12- or KRASG13-mutated LUAD and COAD cell lines that lacked PIK3CA co-mutations. Cell lines with KRASQ61 and/or PIK3CA mutations were insensitive to combination therapy with trametinib and BI-3406. In contrast, deletion of the RAF/MEK/ERK scaffold protein KSR1 prevented treatment-induced TIC upregulation and restored trametinib sensitivity across KRAS mutant cell lines in both PIK3CA-mutated and PIK3CA wildtype cancers. Our findings demonstrate that vertical targeting of RTK/RAS signaling is an effective strategy to target KRAS-mutated cancers, but the specific combination is dependent both on the specific KRAS mutant and underlying co-mutations. Thus, selection of optimal therapeutic combinations in KRAS-mutated cancers will require a detailed understanding of functional dependencies imposed by allele-specific KRAS mutations. Significance Statement Despite advances in the development of oncogene-targeted therapies, resistance invariably occurs. Therapeutic resistance is often due to the presence of intrinsic resistance or the outgrowth of tumor initiating cells, which results in the reactivation of the RTK/RAS pathway. Both dramatically reduce the number of effective treatment options available for patients. Combination therapy targeting up and downstream of RAS will delay the onset of resistance or prevent reactivation of the RTK/RAS pathway, prolonging the progression-free survival and overall survival of patients with lung and colon adenocarcinoma. To accomplish this, we have sought to understand the molecular characteristics of the cancer phenotypes that will most benefit from combination of MEK inhibition with either SOS1 inhibition with BI-3406, or KSR1 disruption by genomic deletion. We ultimately found that SOS1 inhibition increases the efficacy of, and prevents resistance to, Trametinib in KRASG12- and KRASG13-mutated LUAD and COAD cells without a PIK3CA co-mutation, while KSR1 disruption is effective across KRAS mutations, regardless of PIK3CA status.