On April 21, 2026 Revolution Medicines, Inc. (Nasdaq: RVMD), a late-stage clinical oncology company developing targeted therapies for patients with RAS-addicted cancers, reported preclinical data highlighting an innovative new class of mutant-targeted catalytic RAS(ON) inhibitors. These catalytic inhibitors are designed to promote the conversion of mutant RAS in its active RAS(ON) state back to the inactive RAS(OFF) state thereby mimicking the physiological regulation of wild type RAS. This mechanism represents a differentiated approach to inhibition of oncogenic RAS signaling with the goal of addressing tumor resistance mechanisms and extending the durability of current RAS-targeted therapies.
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Results will be presented during a mini symposium at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 21, 2026 (Abstract #6782).
"Additional strategies are needed to counter emergent resistance to RAS inhibitors and further extend clinical benefit for patients with RAS mutant cancers," said Jan Smith, Ph.D., chief scientific officer, Revolution Medicines. "Using our cyclophilin A tri-complex platform, we have discovered a new class of mutant-targeted RAS(ON) catalytic inhibitors designed to stimulate the GTPase activity of mutant RAS variants, a long-sought goal of the RAS research community. In preclinical models, RM-055, an oral compound with this mechanism as the primary driver of RAS pathway inhibition, drove deep and durable tumor regressions across multiple tumor types and overcame resistance to prior RAS inhibition."
At well-tolerated doses, RM-055 demonstrated robust and durable antitumor activity across KRAS G12 mutant xenograft models of pancreatic ductal adenocarcinoma, non-small cell lung cancer, and colorectal cancer. Notably, tumors that had escaped prior RAS inhibitor treatment were sensitive to RM-055, which drove deep and durable regressions warranting further investigation of its potential to counter emergent drug resistance and extend clinical benefit.
Mutant RAS variants causing cancer are relatively insensitive to the natural GTPase-activating proteins (GAPs) that induce physiological inactivation of wild type RAS by stimulating hydrolysis of RAS-GTP to RAS-GDP. Similar to the natural GAPs, RM-055 accelerates the hydrolysis of mutant RAS-GTP to RAS-GDP, converting oncogenic RAS from its active RAS(ON) state to an inactive RAS(OFF) state. A single cyclophilin A:RM-055 binary complex can inactivate multiple mutant RAS proteins.
In preclinical studies, RM-055 significantly reduced RAS-GTP levels in cells, leading to inhibition of downstream RAS signaling and tumor cell proliferation. In vivo RM-055 preferentially suppressed RAS pathway activation in KRAS G12 mutant tumors over normal tissues. This mutant-targeted activity, with a reduced impact on wild-type RAS in normal tissues, suggests the potential for an enhanced therapeutic window and increased flexibility for combination approaches. Moreover, this approach may enable durable pathway suppression even in tumors with increased RAS signaling, a common mechanism of clinical acquired resistance to RAS inhibition.
This novel class of catalytic inhibitors complements Revolution Medicines’ broad portfolio of RAS(ON) multi- and mutant-selective inhibitors that act primarily through steric inhibition of RAS(ON) and further highlights the potential of the cyclophilin A tri-complex platform to enable chemical mechanisms that have not been achieved previously with conventional small molecule strategies.
(Press release, Revolution Medicines, APR 21, 2026, View Source [SID1234664620])