lunresertib (RP-6306)

By integrating CRISPR-Cas9 with functional assays and transcriptomics, our study established a framework for decoding resistance mechanisms and highlights potential therapeutic strategies to enhance RX-3117 efficacy in NSCLC. We demonstrated for the first time that aberrant DNA repair and cell cycle dysregulation led resistance, identifying PKMYT1 as a promising target.

P2, N=28, Active, not recruiting, Canadian Cancer Trials Group | Recruiting --> Active, not recruiting | N=78 --> 28

P1, N=38, Terminated, Repare Therapeutics | Trial completion date: Nov 2026 --> Feb 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2026 --> Feb 2025; Sponsor decided to terminate the study

P1, N=67, Terminated, Repare Therapeutics | N=104 --> 67 | Trial completion date: Apr 2025 --> Aug 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Aug 2024; Sponsor decided to terminate the study

Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage, and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is an effective therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs.

P2, N=78, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E-high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype.

"Foundation Medicine...announced that it has formed a collaboration with Repare Therapeutics, a leading clinical-stage precision oncology company, to provide prospective genomic profiling to patients in Repare’s ongoing Phase I/Ib MYTHIC study (NCT04855656) of lunresertib alone or in combinations in genomically-defined patient populations. The companies are also exploring opportunities to develop FoundationOne CDx, a tissue-based comprehensive genomic profiling test, as a companion diagnostic for the lunresertib program....Foundation Medicine is the global leader in companion diagnostic approvals with approximately 60% of all U.S. companion diagnostic approvals for next generation sequencing testing."

In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.

In a CCNE1-amplified triple-negative cell model (HCC1569), treatment with the PKMYT1 inhibitor RP-6306 significantly reduced tumor growth. CCNE1 amplification in BCs is associated with greater genomic instability and characterizes a group of metastatic BCs with poor response to standard of care therapies. Novel therapies targeting CCNE1-amplified tumors are under evaluation in preclinical and clinical studies.

P1, N=364, Recruiting, Repare Therapeutics | N=180 --> 364

P1, N=24, Active, not recruiting, University Health Network, Toronto | Not yet recruiting --> Active, not recruiting | Initiation date: Dec 2023 --> Mar 2024