Sunday, November 24, 2024
11/24/2024
Project Summary/Abstract PI: Kortum, Robert L. Our data show that RTK−SOS1/2−WT RAS signaling is a critical therapeutic target in RAS-mutated cancers. Our objective is to differentiate between those RAS-mutated cancers in which inhibiting RTK−SOS1/2−WT RAS−effector signaling should be part of an overall effective therapeutic strategy. Direct RAS inhibition as a monotherapy is not effective long-term. RAS proteins show differential activation of RAF and PI3K pathways: HRAS potently activates PI3K but poorly activates RAF, whereas KRAS potently activates RAF but poorly activates PI3K. Because of these differences, inhibiting mutant RAS will not effectively inhibit both the RAF and PI3K pathways. Further, similar to MEK inhibition, mutant RAS inhibition relieves negative feedback controls leading to rapid hyperactivation of RTK−WT RAS signaling. A more comprehensive understanding of the interplay between mutant RAS and RTK−WT RAS signaling is essential to developing rational therapeutic approaches to treat RAS-mutated cancers. We found inhibition of RAS effectors activated poorly by mutant RAS synergizes with and limits resistance to mutant HRAS and KRAS inhibitors. The mutant HRAS inhibitor tipifarnib blocks PI3K signaling and synergizes with MEK inhibitors; covalent KRASG12C inhibitors block MEK signaling and synergize with PI3K inhibitors. We also found that the RASGEFs SOS1 and SOS2 have unique and overlapping functions that promote mutant RAS-driven transformation. SOS1 is critical for mutant RAS activation and SOS1 inhibition augments the efficacy of mutant RAS inhibitors. RTK−SOS2−PI3K signaling protects cells from anoikis and mediates mutant KRAS-driven transformation depending on the PI3K mutational status. SOS2 KO synergizes with MEK inhibitors only in PPIK3CA WT cells, whereas SRC inhibitors synergize with MEK inhibitors only in PIK3CA-mutated cells as was previously reported. These observations suggest the hypothesis that inhibiting RTK−SOS1/2−WT RAS−effector signaling will impair resistance to, and augment, current therapeutics targeting mutated RAS or downstream RAS effectors. We will test this hypothesis with the following Aims: This proposal elucidates the molecular mechanisms through which SOS1/2−WT RAS signaling drives transformation of cancers harboring specific mutant RAS isoforms. We perform studies using a combination of defined genetic model systems and more cancer-relevant systems including CRISPR-modified human cancer cell lines, xenograft studies, and studies using GEMM models to: Determine how WT RAS isoform signaling cooperates with oncogenic RAS to promote oncogenic transformation. Characterize the role of SOS1 in mutant RAS-driven proliferation and transformation, both independently and in combination with SOS2. Establish SOS2 and SRC as therapeutic targets in patient-derived colon cancer organoids based on KRAS and PIK3CA mutation status. Our findings will inform novel therapeutic approaches for eradicating subsets of RAS-mutated tumors with genotype-dependent precision.
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