SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

Abstract

Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2 KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2 KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long term in situ resistance model, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2 KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiary EGFR mutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting

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).…”

“…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 ).…”

“…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 ). Further analysis of 59 NT and 33 SOS2 KO osimertinib-resistant populations showed that SOS2 KO blocked RTK-PI3K dependent osimertinib resistance, and those SOS2 KO populations able to become osimertinib resistant did so by histological transformation.…”

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

“…In addition to SOS1, the RASGEF SOS2 and the phosphatase/adaptor SHP2 represent proximal RTK signaling intermediates and potential therapeutic targets whose inhibition may limit resistance to RTK/RAS pathway inhibitors in LUAD. In parallel studies, we found that inhibiting proximal RTK signaling by either SHP2 inhibition (53) or SOS2 deletion (112) delayed or inhibited the development of osimertinib resistance in EGFR -mutated LUAD cells. Based on these data, we propose proximal RTK inhibition as a therapeutic strategy to delay resistance to RTK/RAS pathway targeted therapies in a majority of LUADs.…”

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

“…In addition to SOS1, the RASGEF SOS2 and the phosphatase/adaptor SHP2 represent proximal RTK signaling intermediates and potential therapeutic targets whose inhibition may limit resistance to RTK/RAS pathway inhibitors in LUAD. In parallel studies, we found that inhibiting proximal RTK signaling by either SHP2 inhibition ( 64 ) or SOS2 deletion ( 123 ) delayed or inhibited the development of osimertinib resistance in EGFR -mutated LUAD cells. Based on these data, we propose proximal RTK inhibition as a therapeutic strategy to delay resistance to RTK/RAS pathway–targeted therapies in a majority of LUADs.…”