Portfolio News
LBA 197 | VS-7375, a non-covalent dual ON/OFF KRAS G12Dinhibitor, displays superior activity to ON-only KRAS G12Dinhibitors in preclinical models of pancreatic cancer
LBA 183 | Strong durable tumor regressions with the KRAS G12D (ON/OFF) inhibitor VS-7375 in combination with PRMT5 inhibition in MTAP-deleted/KRAS G12D-mutant pancreatic cancer
Poster 7100 | VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with potent anti-tumor activity as a single agent and in combination with other agents
Enhanced anti-tumor activity versus other KRAS/RAS inhibitors (RMC-9805 and RMC-6236)
In the preclinical research conducted in models harboring KRAS G12D mutant tumors, GFH375 alongside with comparators RMC-9805 and RMC-6236 were administered at animal dose levels that correlate with their respective human RP2D; GFH375 exhibited significantly greater tumor growth inhibition, across KRAS G12D-mutant PDAC, NSCLC and colorectal cancer (CRC) models.
In G12D-mutant PDAC cellular assays, GFH375 was 5-48 fold more potent and selective than RMC-9805; following drug washout, GFH375 suppressed pERK signaling more durably than RMC-9805, and maintained superior, longer lasting ERK inhibition at a 10 fold lower concentration.
Strong rationale for combination regimens in advanced KRAS-mutant cancers
In PDAC, NSCLC and CRC models, combination regimens demonstrated enhanced anti-tumor activity versus single-agent therapy. The combo regimens include GFH375 with cetuximab, or with FAK inhibitor ± the RAF/MEK clamp avutometinib, or with PRMT5 inhibitors (particular benefit observed in KRAS G12D–mutant, MTAP-deleted PDAC).
Prior published research demonstrated that MTA-cooperative PRMT5 inhibitors selectively address MTAP-deleted, KRAS-mutant pancreatic cancers. Data from Verastem’s preclinical research further validated the absence of cross-resistance between RAS and PRMT5 inhibitors, supporting sequential or combination approaches for the 25% of KRAS-mutant PDAC patients with concurrent MTAP deletion; PRMT5 and KRAS govern independent signaling pathways and distinct transcriptional programs yet converge on core PDAC survival pathways, including cell-cycle progression and MYC-driven oncogenesis.
Mechanistic analyses linked dysregulated MYC signaling to PRMT5 inhibitor resistance; while RAS inhibition reduced viability of PRMT5i-resistant cells, it no longer suppressed MYC expression. In PDAC models, GFH375 exerted more durable inhibition of MYC-driven gene transcription than RMC-9805 and RMC-6236, further strengthening the rationale for combining GFH375 with PRMT5 inhibitors to overcome potential resistance.
Mechanistic insights into the development and reversibility of therapeutic resistance
Resistance profiling was performed in escalating concentration and in a 30-day drug washout culture paradigm parallelly to evaluate the reversibility of resistance in PDAC cell lines; high concentration of GFH375 still achieved IC₅₀ activity in some resistant cell line, and the acquired resistance was partially reversible as 30 days of drug withdrawal restored partial sensitivity to GFH375 in all cell lines.
GFH375 also induced rapid and sustained suppression of KRAS effector signaling and ERK activation, including durable inhibition of p-ERK, p-AKT and p-S6, reflecting robust and long-lasting control of both MAPK and PI3K pathways. Mechanistic studies confirmed that the potential resistance mechanisms were heterogeneous across models, with RAF-MEK-ERK inhibitors retaining anti-proliferative activity in some cell lines.
