Dr Jänne on the Investigation of RMC-6291 in KRAS G12C-Mutated Solid Tumors

Pasi A. Jänne, MD, PhD, director, Lowe Center for Thoracic Oncology, director, Belfer Center for Applied Cancer Science, director, Chen-Huang Center for EGFR Mutant Lung Cancers, senior physician, Dana-Farber Cancer Institute; professor of medicine, Harvard Medical School, discusses the mechanism of action of the novel KRAS G12C RAS(ON) inhibitor RMC-6291, which is being evaluating for the treatment of patients with KRAS-mutated solid tumors.

RMC-6291 functions by inhibiting proteins that facilitate the development of cancer cells characterized by a KRAS G12C mutation, and its action in blocking these proteins may impede or halt the progression of cancer. RMC-6291 is administered orally, and the agent is being evaluated as a monotherapy in a multicenter, open-label, dose-escalation and -expansion phase 1/1b trial (NCT05462717) in patients with advanced KRAS G12C–mutant solid tumors.

KRAS, a key protein involved in cell signaling, exists in 2 primary states: an active ON form and an inactive OFF form, Jänne begins. These states are crucial for controlling cellular processes, and KRAS cycles between these states to regulate cell growth and division, he says, adding that adagrasib (Krazati) and sotorasib (Lumakras) function by targeting the inactive OFF form of KRAS. When these drugs bind to the inactive state of KRAS, they effectively trap it in that state, hindering its activity, Jänne explains. However, this mechanism may create an opening for the tumor to develop resistance against these drugs, he says.

Additionally, even in the presence of adagrasib and sotorasib, other cellular signals may continue to transmit through the active form of KRAS, limiting the effectiveness of these treatments. RMC-6291 operates via a different approach, Jänne emphasizes. This medication targets a cellular protein commonly found in cancer cells known as cyclophilin A. By binding to cyclophilin A, RMC-6291 creates a complex that interacts with the active form of KRAS, forming a tricomplex, he states. This effectively impedes the active form of KRAS, preventing it from initiating its signaling processes within the cell, Jänne says.

What distinguishes RMC-6291 from adagrasib and sotorasib is its ability to block the active ON form of KRAS, he continues. While the earlier-generation drugs focus on the inactive state of KRAS, RMC-6291 specifically hinders the active state, providing a different and potentially complementary approach to preventing KRAS-driven cancer progression, Janne states. This novel mechanism offers the potential for more comprehensive inhibition of KRAS signaling pathways, and it may improve the effectiveness of treatments against KRAS G12C–mutated solid tumors, he concludes.