Piotr Wysocki, Professor of Medicine and Head of the Department of Oncology at Jagiellonian University Hospital, shared on LinkedIn:

“A recent study published in Nature delved into the preclinical activity of the RMC-7977 molecule, a highly selective inhibitor of GTP-bound forms of KRAS, HRAS, and NRAS in pancreatic ductal adenocarcinoma models (PDAC). RMC-7977 stands out with its unique mechanism of action, leading to efficient inhibition of downstream signaling from activated, both wild-type and mutated KRAS, NRAS, and HRAS kinases. The authors chose the PDAC model due to the high prevalence (90% of human PDACs) of KRAS mutations.

RMC-7977 induced profound apoptosis of PDAC cells both in vitro and in vivo, along with sustained proliferative arrest without any significant impact on normal tissues (normal cells demonstrated only transiently decreased proliferation, with no evidence of apoptosis). In PDAC cell line-derived xenografts, regression (30-98% of initial volume) of tumors was observed in 70% of cases.

The authors have also identified mechanisms of resistance to TMC-7977, which was related to the activation of an evolutionarily conserved signaling pathway (HIPPO) and could be overcome by inhibiting TEAD (blocking YAP/TAZ/TEAD interaction).”

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Source: Piotr Wysocki/LinkedIn