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

Abstract

AbstractKRAS 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 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 receptor tyrosine kinase (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 enhanced the efficacy of, and prevented resistance to, the MEK inhibitor trametinib inKRAS-mutated lung (LUAD) and colorectal (COAD) 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 inKRASG12- orKRASG13-mutated LUAD and COAD cell lines that lackedPIK3CAco-mutations. Cell lines withKRASQ61and/orPIK3CAmutations were insensitive to combination therapy with trametinib and BI-3406. In contrast, deletion of the RAF/MEK/ERK scaffold proteinKSR1prevented drug-induced TIC upregulation and restored trametinib sensitivity across all testedKRASmutant cell lines in bothPIK3CA-mutated andPIK3CAwildtype cancers. Our findings demonstrate that vertical targeting of RTK/RAS signaling is an effective strategy to targetKRAS-mutated cancers, but the specific combination is dependent both on the specific KRAS mutant and underlying co-mutations. Thus, selection of optimal therapeutic combinations inKRAS-mutated cancers will require a detailed understanding of functional dependencies imposed by allele-specific KRAS mutations.Significance StatementWe provide an experimental framework for evaluating both adaptive and acquired resistance to RAS pathway-targeted therapies and demonstrate how vertical inhibition of RAS signaling enhances the effectiveness of MEK inhibitors inKRAS-mutated cancer cells. Targeting RAS pathway signaling intermediates SOS1 or KSR1 inhibited tumor initiating cell formation to prevent trametinib resistance. The contribution of either effector to resistance was dependent upon the mutational landscape: SOS1 inhibition synergized with trametinibKRASG12/G13-mutated cells expressing WT PI3K but not inKRASQ61-mutated cells or ifPIK3CAis mutated.KSR1deletion is effective in cells that are unresponsive to SOS1 inhibition. These data show that optimal therapeutic combinations require a detailed understanding of functional dependencies imposed both by allele-specificKRASmutations and specific co-mutations.