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

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 (SOS2 ) 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.

SOS2 regulates the threshold of mutant -dependent oncogenesis.

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). deletion sensitized -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.

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

Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Preclinical studies that identify synergistic combinations enhance therapeutic efficacy to target intrinsic resistance, however, methods to study acquired resistance in cell culture are lacking. Here, we describe a novel in situ resistance assay (ISRA), performed in a 96-well culture format, that models acquired resistance to RTK/RAS pathway targeted therapies.

Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer.

Drug treatment of 3D cancer spheroids more accurately reflects in vivo therapeutic responses compared to adherent culture studies. In EGFR-mutated lung adenocarcinoma, EGFR-TKIs show enhanced efficacy in spheroid cultures. Simultaneous inhibition of multiple parallel RTKs further enhances EGFR-TKI effectiveness.

Anchorage-independent growth conditions reveal a differential SOS2 dependence for transformation and survival in -mutant cancer cells.

The RAS family of genes (, and ) is mutated in around 30% of human tumours. Wild-type RAS isoforms play an important role in mutant RAS-driven oncogenesis, indicating that RasGEFs may play a significant role in mutant RAS-driven transformation. We recently reported a hierarchical requirement for SOS2 in mutant RAS-driven transformation in mouse embryonic fibroblasts, with KRAS>NRAS>HRAS (Sheffels et al.