Monte Rosa Therapeutics presented compelling preclinical data at the American Association for Cancer Research (AACR) Annual Meeting 2025 demonstrating the potential of its highly selective cyclin-dependent kinase 2 (CDK2)-directed molecular glue degrader, MRT-51443, for treating hormone receptor-positive/HER2-negative breast cancer. The data, presented on April 30 in Chicago, showed superior anti-tumor activity when combined with standard care therapies.
Superior Efficacy in Preclinical Models
The most striking results came from in vivo studies where MRT-51443 combined with CDK4/6 inhibition and anti-estrogen therapy achieved dramatically deeper tumor regressions compared to current standard of care. In the MCF7 breast cancer model, the triple combination of MRT-51443 plus ribociclib plus fulvestrant demonstrated median tumor growth of -77% versus only -3% for the standard ribociclib plus fulvestrant combination. Similarly, in the T47D model, the triple combination achieved -61% median tumor growth compared to -10% for standard care.
"In preclinical models of HR-positive/HER2-negative breast cancer, the combination of MRT-51443 with a CDK4/6 inhibitor and anti-estrogen therapy drove robust tumor regressions, demonstrating notably deeper tumor responses than the standard of care combination alone," said Sharon Townson, Ph.D., Chief Scientific Officer of Monte Rosa Therapeutics.
Addressing CDK4/6 Inhibitor Resistance
The research addresses a critical clinical challenge in breast cancer treatment. While CDK4/6 inhibitors combined with endocrine therapy represent FDA-approved standard care for HR-positive/HER2-negative breast cancer, many patients eventually develop resistance as their tumors become reliant on the CDK2 pathway. CDK2 functions as a key driver of cell cycle progression, working in coordination with CDK4 and CDK6 to promote cancer cell proliferation.
MRT-51443 demonstrated the ability to delay resistance to CDK4/6 inhibition in vitro studies, a finding that could have significant clinical implications for extending treatment durability. The molecular glue degrader showed highly selective degradation of CDK2 with no detectable off-target activity, potentially avoiding toxicities associated with less selective CDK2 inhibitors.
Molecular Glue Degrader Technology
Monte Rosa's approach utilizes molecular glue degrader (MGD) technology, which represents a novel class of small molecule protein degraders. The company's proprietary QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) discovery engine combines AI-guided chemistry, diverse chemical libraries, structural biology, and proteomics to identify degradable protein targets and design MGDs with unprecedented selectivity.
The cellular assays demonstrated that MRT-51443 induced deep CDK2 degradation, resulting in CDK2-dependent cancer cell growth inhibition. This selective targeting approach showed superior selectivity compared to several clinical-stage small molecule CDK2 inhibitors currently in development.
Clinical Development Timeline
Monte Rosa anticipates submitting an Investigational New Drug (IND) application for their cell cycle program in 2026. The company believes their MGD approach could provide more sustained responses in this difficult-to-treat patient population while avoiding toxicities typically associated with limited selectivity of CDK2 inhibitors.
"The degree to which CDK2 degradation with MRT-51443 delayed resistance to CDK4/6 inhibition in vitro was also striking, as patients treated with CDK4/6 inhibitors often relapse because their tumors become reliant on the CDK2 pathway," Townson noted.
Strategic Partnerships and Pipeline
Monte Rosa has established significant industry partnerships, including a global license agreement with Novartis to advance VAV1-directed molecular glue degraders and a strategic collaboration with Roche to discover and develop MGDs against targets in cancer and neurological diseases previously considered undruggable. The company's pipeline spans oncology, autoimmune and inflammatory diseases, positioning it at the forefront of the emerging protein degradation field.
The preclinical data presented at AACR 2025 represents a significant step forward in addressing the unmet medical need for patients with HR-positive/HER2-negative breast cancer who develop resistance to current standard therapies, potentially offering a new therapeutic approach that could improve clinical outcomes in this challenging patient population.
