As KRAS G12C inhibitors progress through the clinic, there remains a need for additional modalities to target other oncogenic KRAS mutations. Targeting its RasGEF, SOS1, represents a pan-KRAS modality to treat KRAS-driven cancers. Here, Begovich and colleagues present a SOS1 bifunctional degrader, BTX-6654, that demonstrates potent SOS1 degradation and inhibits downstream signaling and proliferation in a mechanism-specific manner. BTX-6654 displays tumor growth inhibition as a single agent and synergizes with KRAS G12C and MEK inhibitors in vitro and in KRAS G12C xenograft models, highlighting its promise to treat KRAS mutant cancers for monotherapy and combination approaches.

Interleukin-12 (IL-12) has significant therapeutic potential in immunologically ‘cold’ tumors due to its ability to induce a ‘hot’ immune microenvironment by enhancing immune cell recruitment and effector function; however, considerable toxicity has hindered its clinical development. XTX301 is a half-life extended, tumor-activated IL-12 molecule designed to concentrate its activity in the tumor while limiting...

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