SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma

• Published in: Molecular oncology 2024-03, Vol.18 (3), p.641-661
• Main Authors: Theard, Patricia L., Linke, Amanda J., Sealover, Nancy E., Daley, Brianna R., Yang, Johnny, Cox, Katherine, Kortum, Robert L.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; acquired resistance; Adenocarcinoma; AKT protein; c-Met protein; Cancer; Care and treatment; Clonal deletion; Drug therapy; EGFR‐TKI; Epidermal growth factor; Epidermal growth factor receptors; Feedback; Fibroblasts; Guanine nucleotide exchange factor; Hepatocyte growth factor; Kinases; Lung cancer; Mutation; osimertinib; Phenotypes; PI3K; Protein-tyrosine kinase receptors; Proteins; RAS; SOS2; Stem cells; Tumors; Tyrosine; Tyrosine kinase inhibitors; Variance analysis
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13564

Son of sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic receptor tyrosine kinase (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 tyrosine kinase inhibitor (EGFR‐TKI) osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion (SOS2KO) sensitized EGFR‐mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit phosphatidylinositol 3‐kinase (PI3K)/AKT pathway activation, oncogenic transformation, and survival. Bypassing RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR‐TKIs; SOS2KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET‐driven bypass model, SOS2KO inhibited hepatocyte growth factor (HGF)‐stimulated PI3K signaling to block HGF‐driven osimertinib resistance. Using a long‐term in situ resistance assay, most 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 SOS2KO cultures that became osimertinib resistant primarily underwent non‐RTK‐dependent epithelial–mesenchymal transition (EMT). Since bypassing RTK reactivation and/or tertiary EGFR mutations represent most osimertinib‐resistant cancers, these data suggest that targeting proximal RTK signaling, here exemplified by SOS2 deletion, has the potential to delay the development osimertinib resistance and enhance overall clinical responses for patients with EGFR‐mutated LUAD. RTK‐dependent PI3K/AKT activation, associated with a hybrid epithelial/mesenchymal phenotype, is a hallmark of EGFR‐TKI‐resistant lung adenocarcinoma (LUAD). This study shows that SOS2 deletion reduces the threshold for PI3K/AKT inhibition, effectively reducing the frequency of RTK/AKT‐pathway‐driven EGFR‐TKI‐resistant cultures. These findings suggest that proximal RTK pathway inhibition has the potential to enhance clinical responses for patients with EGFR‐mutated LUAD.