SOS1 inhibition suppresses the emergence of osimertinib resistance to generate a durable response in <i>EGFR</i> -mutant lung cancer

Osimertinib is the mainstay of therapy for patients with non-small cell lung cancer (NSCLC) driven by the receptor tyrosine kinase (RTK) EGFR. In most patients, however, therapeutic pressure promotes RTK-dependent mechanisms that support tumor cell survival and the emergence of osimertinib resistance. Here, we found that inhibiting the proximal RTK signaling intermediate SOS1 promoted continued osimertinib efficacy in sensitive cells and restored sensitivity in cells with acquired resistance. In three-dimensional spheroid cultures of naïve NSCLC cells, SOS1 inhibition enhanced osimertinib potency by limiting the reactivation of RTK-dependent adaptive Ras effectors. SOS1 inhibition resensitized drug-tolerant persister cells to osimertinib, and knockout or inhibition of SOS1 reduced the frequency of tumor-initiating cells to curb spheroid growth in situ and tumorigenesis in vivo. SOS1 inhibition further limited the development of acquired osimertinib resistance and resensitized resistant cells to osimertinib. In mice, tumors regressed nearly completely when treated with either osimertinib or a combination of osimertinib and a SOS1 inhibitor, with the combination providing a slightly greater effect. However, only the combination delayed tumor regrowth after treatment removal. Our data provide a mechanistic rationale for the clinical investigation of combining SOS1 inhibitors with osimertinib to achieve more durable responses and suppress resistance in NSCLC.