Targeting Polθ Helicase with RP-3467: Preclinical Validation and Clinical Response in a g BRCA1 ovarian cancer patient with an acquired PARPi resistance mutation in TP53BP1
Year: 2026
Type: preprint
Abstract: ABSTRACT Homologous recombination (HR) deficiency underlies a range of cancers, and PARP inhibitors (PARPi) targeting this vulnerability have demonstrated clinical efficacy in BRCA1/2 -mutant tumors. However, resistance mechanisms and tolerability issues limit their long-term clinical effectiveness. Here, we characterize RP-3467, a novel, selective small-molecule inhibitor targeting the ATPase domain of DNA polymerase theta (Polθ), the key mediator of the error-prone microhomology-mediated end joining (MMEJ) pathway. We demonstrate that RP-3467 potently suppresses Polθ enzymatic activity, abrogates MMEJ, and disrupts mitotic DNA repair in HR-deficient (HRD) models, inducing synthetic lethality. In preclinical studies, we show that RP-3467 synergizes strongly with PARPi (olaparib and rucaparib), achieving sustained tumor regression across multiple xenograft and patient-derived xenograft (PDX) models without added systemic toxicity. Mechanistically, we find that RP-3467 increases mitotic DNA damage in vivo, as evidenced by elevated micronuclei and CIP2A foci. RP-3467 was evaluated in a phase 1 clinical trial ( NCT06560632 ) and has shown preliminary signs of clinical activity. A heavily pretreated germline BRCA1 -mutant ovarian cancer patient achieved a confirmed partial response to RP-3467 plus olaparib (RECIST v1.1), with retrospective profiling revealing a TP53BP1 loss-of-function mutation previously linked to both PARPi resistance and POLQ dependency. Although broader clinical validation is needed, these early findings suggest that Polθ inhibition has the potential to address PARPi resistance and offer therapeutic benefit in HRD cancers.
Source: medRxiv
Authors: Ezra Y. Rosen, Marie-Claude Mathieu, Gino B. Ferraro, Philippe Mochirian, Claude Godbout, Hugo Poirier, Sara Fournier, Danielle Henry, Hyeyeon Kim, Robert Papp, Shou Yun Yin, Marie-Eve Leclaire, Robert Houle, Parham Nejad, Joseph D. Schonhoft, Karl E. Zahn, W. Cameron Black, Michel Gallant, Insil Kim, Danielle Ulanet, Paul Basciano, Artur Veloso, Victoria Rimkunas, Timothy A. Yap, Robin Guo, Nicholas Mai, Maria Koehler, Michael Zinda, Anne Roulston, Michal Zimmermann, Stephen J. Morris, Agnel Sfeir
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Transcriptomic mechanisms underlying the immune modulating function and therapeutic efficacy of PARP inhibitors, Investigating PolQ-mediated alternative NHEJ in breast cancer, MSK SPORE in Genomic Instability in Breast Cancer, Cancer Center Support Grant, Investigating the role of Microhomology-Mediated End-Joining (MMEJ) in Mitosis and its impact on drug resistance, The University of Texas MD Anderson Cancer Center SPORE in Ovarian Cancer
OpenAlex ID: W7214044847