image: (A, B) Western blotting analysis of FASN and PARP1 expression in stable MDA-MB-436 cells overexpressing FASN (MDA-MB-436/FASN) and MDA-MB-231 cells with FASN knockdown (MDA-MB-231/shFASN) along with their respective control cells transfected with vector (Vec) and scrambled ShRNA (ShFASN).
(C–F) Concentration-dependent survival curves of MDA-MB-436/FASN cells, MDA-MB-231/shFASN cells, and their respective control cells. Their relative resistance factor (RRF) against talazoparib and 5HLS was assessed using the methylene blue survival assay to derive IC50 values and calculated using the formula RRF = IC50(FASN or shFASN)/IC50(Vec or Scr). The data are presented as mean ± standard deviation. n = 3; ∗∗P < 0.01 and ∗P < 0.05.
Credit: Sophia Josephraj, Chao J. Wang, Qingbin Cui, Zizheng Dong, Jing-Yuan Liu, Jian-Ting Zhang
While poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), such as olaparib and talazoparib, have been approved for other BC types, “their therapeutic impact on BRCA wild-type TNBC remains modest due to a lack of synthetic lethality and inherent resistance mechanisms.”
A recent study published in the Genes & Diseases journal by researchers from University of Toledo College of Medicine and Life Sciences showed that targeting fatty acid synthase (FASN)—the sole mammalian cytosolic de-novo lipid synthesis enzyme essential for cancer cell survival but not for normal cells—may overcome PARPi resistance and induce artificial synthetic lethality in TNBC.
The authors had previously demonstrated that: (i) FASN up-regulates PARP expression; (ii) proton pump inhibitors (PPIs)—lansoprazole and its metabolite, 5-hydroxy lansoprazole sulfide (5HLS)—reduce PARP1 expression by inhibiting FASN; and (iii) PPIs synergize with DNA-damaging agents by regulating PARP1 expression and impairing non-homologous end joining (NHEJ) repair of DNA damage. Based on these findings, the authors hypothesized that PPIs synergize with PARPi to induce an artificial synthetic lethality in BRCA wild-type TNBC cells, thereby potentially expanding PARPi application to a broader TNBC population.
Initial experiments involving TNBC cell lines with stable FASN overexpression or knockdown, and treated with different concentrations of talazoparib, showed that FASN-overexpressing cells were resistant to the drug, while FASN-knockdown cells showed little resistance, suggesting that FASN expression and activity contribute to the cellular response to talazoparib. The authors then performed combination analyses of 5HLS with olaparib or talazoparib, showing that FASN inhibition with 5HLS increases PARPi sensitivity. Similar results were observed with lansoprazole, the parent compound of 5HLS, concluding that both lansoprazole and its metabolite 5HLS sensitize TNBC cells to PARPi and synergize with PARPi likely by inhibiting FASN.
Further experiments revealed that the expression levels of FASN and PARP1 significantly affect cellular response to each agent individually and also influence the synergism between FASN inhibitors and PARPi. Additionally, 5HLS + talazoparib synergistically inhibited NHEJ repair activity, leading to increased DNA damage accumulation and apoptosis.
The authors also showed that 5HLS facilitates PARP1 recruitment to chromatin or its retention and synergizes with talazoparib, enhancing talazoparib-induced PARP1 trapping. Subsequent experiments revealed that FASN regulates BRCA1 expression and activation in a palmitate-dependent mechanism and that PARPi-induced inhibition of FASN expression/function creates an artificial synthetic lethality in BRCA1 wild-type TNBC cells. These findings were validated in vivo.
In conclusion, this study provides mechanistic insights into the role of FASN in BRCA1-TNBC and highlights that targeting FASN with PPIs and their metabolites in combination with PARPi is a novel therapeutic approach to overcome PARPi resistance in this malignancy.
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