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

Abstract

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.

In situ modeling of acquired resistance to RTK/RAS pathway targeted therapies

“…The effect of SOS1 inhibition on trametinib resistance was similarly RTK-PI3K pathway dependent, as PIK3CA comutations ablated the ability of SOS1 inhibition to limit osimertinib resistance. The importance of RTK-PI3K signaling to both osimertinib (51,56) and trametinib (52) resistance reinforces the hypothesis that LUADs are RTK/RAS pathway addicted (57)(58)(59)(60)(61). Our findings that pan-RTK inhibition, via blocking SHP2, SOS1, or SOS2, blocks resistance to two distinct RTK/RAS pathway inhibitors in LUAD suggests that inhibiting proximal RTK signaling may be general strategy to limit resistance to RKT/RAS pathway inhibitors in LUAD (61).…”

“…In another study, we found that SOS1 inhibition with BI-3406 ( 55 ) both enhanced the efficacy of and limited the development of acquired resistance to the MEK inhibitor trametinib in KRAS G12 -mutatated LUAD cells ( 52 ). The effect of SOS1 inhibition on trametinib resistance was similarly RTK-PI3K pathway dependent, as PIK3CA co-mutations ablated the ability of SOS1 inhibition to limit osimertinib resistance.…”

“…Downstream of RTKs, the SHP2 phosphatase acts as an adaptor to recruit the RASGEFs SOS1 and SOS2 to receptor complexes and promote RAS activation. In two parallel sets of studies, proximal RTK inhibition, via either SOS2 deletion ( 51 ) or SOS1 inhibition ( 52 ), similarly limited RTK-driven acquired resistance in LUAD. In addition to SHP2 inhibition, SOS2 KO significantly limited the overall percentage of EGFR -mutated LUAD populations able to become osimertinib resistant ( 51 ).…”

SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

“…Thus, in addition to SOS2, SHP2 and SOS1 are RTK signaling intermediates and potential therapeutic targets whose inhibition might limit resistance to RTK/RAS pathway inhibitors in LUAD. In two parallel sets of studies, we found that inhibition of proximal RTK signaling via (i) the SHP2 inhibitors RMC-4550 or SHP099 significantly inhibited osimertinib resistance in EGFR -mutated LUAD cells (Sealover, Theard et al, submitted) and (ii) the SOS1 inhibitor BI-3406 significantly inhibited MEK-inhibitor resistance in KRAS G12 -mutatated LUAD cells ( 69 ). Based on these data, we propose that inhibition of proximal RTK signaling could be a common mechanism to prevent resistance to targeted therapies in a majority of LUAD.…”

“…In addition to SOS2 KO, inhibition of proximal RTK signaling via the SHP2 inhibitors RMC-4550 or SHP099 significantly inhibited osimertinib resistance in EGFR -mutated LUAD cells ( 30 ). The SOS1 inhibitor BI-3406 significantly inhibited acquired resistance to the KRAS G12C ( 71 ) or MEK ( 72 ) inhibitors in KRAS G12 -mutatated LUAD cells. Based on these data, we propose that inhibition of proximal RTK signaling could be a common mechanism to prevent resistance to targeted therapies in a majority of LUAD.…”