Jian-Ting Zhang

Despite advances in cancer treatment with targeted therapies and immunotherapies, triple-negative breast cancer (TNBC) has not significantly benefited from these developments. Although poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved for breast cancer, their clinical use is largely limited to the small subset of HER2-negative patients with germline BRCA1/2 mutations, and resistance is frequently observed. Previously, we demonstrated that proton pump inhibitors (PPIs), including lansoprazole and its metabolite, 5-hydroxy lansoprazole sulfide (5HLS), reduce PARP1 expression by inhibiting fatty acid synthase (FASN), a key enzyme in de-novo lipid synthesis. We also found that PPIs synergize with DNA-damaging agents by regulating PARP1 expression and impairing non-homologous end joining (NHEJ) repair of DNA damage. These findings led to the hypothesis that PPIs synergize with PARPi independently of BRCA mutation, potentially expanding the utility of PARPi to a broader TNBC population. In this study, we show that FASN contributes to PARPi resistance, and that lansoprazole and 5HLS strongly synergize with olaparib and talazoparib in both BRCA1-mutant and wild-type TNBC cells. This synergy occurs through FASN inhibition and subsequent impairment of NHEJ repair of double-strand breaks induced by PARPi trapping. 5HLS also facilitates PARPi-induced PARP1 trapping and inhibits BRCA1 expression by inhibiting FASN, contributing to the synergy with PARPi in both BRCA1 wild-type and mutant TNBC cells. Together, these findings suggest that inhibiting FASN with PPIs creates an artificial synthetic lethality, providing a rationale for combining PPIs with PARPi to expand their utility to TNBC patients without germline BRCA1 mutations and to overcome PARPi resistance.

Survivin, a homodimeric protein and a member of the IAP family, plays a vital function in cell survival and cycle progression by interacting with various proteins and complexes. Its expression is upregulated in cancers but not detectable in normal tissues. Thus, it has been regarded and validated as an ideal cancer target. However, survivin is "undruggable" due to its lack of enzymatic activities or active sites for small molecules to bind/inhibit. Academic and industrial laboratories have explored different strategies to overcome this hurdle over the past two decades, with some compounds advanced into clinical testing. These strategies include inhibiting survivin expression, its interaction with binding partners and homodimerization. Here, we provide comprehensive analyses of these strategies and perspective on different small molecule survivin inhibitors to help drug discovery targeting "undruggable" proteins in general and survivin specifically with a true survivin inhibitor that will prevail in the foreseeable future.