Friday, May 9, 2025
5/9/2025
Molecular basis and targeting of FASN in expanding PARPi utility for TNBC - SUMMARY While targeted therapies and immunotherapies have improved outcomes for some cancers, patients with triple-negative breast cancer (TNBC) have seen limited benefits from these advances and often suffer from the toxicities of ineffective chemotherapeutics, including platinum-based drugs. This highlights a critical unmet need in TNBC treatment. Although PARP inhibitors (PARPi’s) including olaparib and talazoparib have been approved for treating HER2-negative breast cancers with BRCA mutations, most TNBC patients do not benefit from this new treatment and PARPi resistance frequently develops, further limiting the benefits of PARPi’s. Recent findings indicated that fatty acid synthase (FASN) regulates both NHEJ and HR repair of double strand DNA breaks and, thus, may affect cellular response to PARPi. FASN is the sole cytosolic enzyme responsible for de- novo synthesis of palmitate. Given the abundant dietary intake of free fatty acids in a modern Western diet, normal cells, except those in lipogenic tissues, do not rely on FASN. In contrast, breast cancer cells exhibit high FASN levels and their survival and proliferation require de-novo fatty acid synthesis. Targeting FASN to inhibit lipogenesis induces apoptosis selectively in cancer cells both in vitro and in vivo with minimal effect on normal cells. Furthermore, high FASN expression correlates with poor prognosis, metastasis, and recurrence in breast cancer, making it an ideal target for drug discovery. Our recent work demonstrated that proton pump inhibitors (PPIs) effectively inhibit human FASN. Retrospective analyses of electronic medical records revealed that PPI usage significantly improves overall survival of breast cancer patients including those with TNBC. A phase II clinical trial further confirmed that PPIs inhibit FASN function, benefiting TNBC patients. Our preliminary studies suggest that FASN contributes to PARPi resistance by regulating PARP1 and BRCA1 expression. Moreover, PPIs not only inhibit TNBC cell survival but also synergizes with PARPi’s, regardless of BRCA status. Thus, we hypothesize that (1) FASN contributes to PARPi resistance by upregulating PARP1 and BRCA1 expression to increase NHEJ and HR repair of DSB, and (2) PPIs synergize with PARPi by targeting FASN to overcome PARPi resistance and create an artificial synthetic lethality in BRCA proficient TNBC cells. To this end, we will accomplish three specific aims to (1) determine the molecular basis of PPI inhibition of FASN, (2) determine the molecular mechanism of FASN action in PARPi resistance, and (3) determine the synergism of PPI combination with PARPi in both BRCA1 mutant and wild-type TNBC cells. The successful outcome of this study will help establish FASN overexpression in TNBC cells as a mechanism of PARPi resistance and repurpose PPIs to overcome PARPi resistance by targeting FASN. Furthermore, it will provide supporting evidence and scientific basis for a clinical trial testing synergistic combination of PPI with PARPi, offering a novel treatment option for TNBC patients irrespective of their BRCA status and potentially transforming the TNBC treatment landscape.
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