Pre-Clinical Evaluation of a Highly Selective SMARCA2 Degrader in Therapy-Resistant Triple-Negative Breast Cancer

/ ABSTRACT Patients who achieve a pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) have good outcomes, while patients with residual disease (RD) are at high risk of recurrence and death. Patients who achieve a pathologic complete response (pCR) to NAST have good outcomes, while patients with residual disease (RD) are at high risk of recurrence and death. More effective therapies are needed for TNBC that is resistant to standard-of-care NAST. One of the barriers in developing more effective therapies for chemoresistant TNBC is inadequate molecular characterization of RD and lack of understanding of the mechanisms that lead to NAST resistance. We have leveraged our highly productive TNBC neoadjuvant systemic therapy clinical trial pipeline to uncover convergent mechanisms of therapeutic resistance. Using this approach, we have identified an adaptive switch in utilization of the mutually exclusive SWI/SNF ATPase subunits SMARCA4 and SMARCA2 between paired pre-treatment and post-NAST TNBCs. We found that increased expression of SMARCA4 in pre- treatment samples was associated with achieving pathologic complete response and that virtually all RD samples, regardless of NAST regimen, showed profound suppression of SMARCA4 expression and induction of SMARCA2-dependent gene expression programs. SMARCA4-deficient cells become dependent on the SMARCA2 paralog to maintain cellular viability, and loss of SMARCA2 in SMARCA4-deficient cells is synthetic lethal. There has been success in selectively targeting SMARCA2 using proteolysis-targeting chimeras (PROTACs), including PRT3789 (Prelude Therapeutics, Inc.), which has shown clinical efficacy in SMARCA4- deficient cancers (NCT05639751). We hypothesize that SMARCA2 paralog dependency is an exploitable therapeutic vulnerability in therapy-resistant TNBC, and that PRT3789 will be an effective treatment for chemoresistant TNBC. In this proposal, we aim to use two isogenic carboplatin-sensitive and carboplatin- resistant pre-clinical models of TNBC to evaluate the efficacy of PRT3789 alone and in combination with carboplatin in vitro and in vivo. We also propose to perform transcriptomic and proteomic/phosphoproteomic analysis of xenograft tumors after treatment with PRT3789, carboplatin, or the combination of PRT3789 and carboplatin to elucidate the anti-neoplastic mechanisms of PRT3789. The proposed study is highly clinically significant, as the hypothesis was generated from unbiased molecular characterization of TNBC patients’ tumors treated prospectively on high-impact neoadjuvant therapy trials, the phenotype appears to be shared amongst virtually all patients with RD regardless of NAST regimen, and this pathway is amenable to therapeutic intervention with an agent that has already shown efficacy in human trials. If successful, this pre-clinical work will pave the way for rapid development of an interventional trial of PRT3789 in high-risk TNBC patients with RD. Project Number: 1R21CA307485-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Priyanka Sharma (+1 co-PI) | Institution: UNIVERSITY OF KANSAS MEDICAL CENTER, KANSAS CITY, KS | Award Amount: $398,544 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-X (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11283698