He/Him/His
Job Title
Postdoctoral Research Fellow
Academic Rank
Fellow or Postdoc
Department
Medicine
Pulmonary
Authors
Samer Salem*, MD, Nadine Mahmoud, MD, Joelle Chami, MD, Michel Alchoueiri, MD, MSc, Melissa Daou, MD, MSc, Hadi Mansour, MD, Damir Khabibullin, MS, Thai Ho, MD, PhD, Carmen Priolo, MD, PhD, Elizabeth Henske, MD
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There are no proven therapies for metastatic or unresectable Chromophobe renal cell carcinoma (ChRCC). Ferroptosis is an iron-dependent form of cell death characterized by peroxidation of polyunsaturated fatty acids. We previously discovered that ChRCC is hypersensitive to ferroptosis induced by the disruption of glutathione homeostasis, a cellular antioxidant, via inhibition of SLC7A11 and GPX4 (PNAS, 2018, 2022). Ferroptosis suppressor protein (FSP1) is a glutathione-independent suppressor of ferroptosis. FSP1’s role in ChRCC is unexplored.
DepMap (484 cell lines) and Cancer Therapeutics Response Portal (860 cell lines) data revealed that FSP1 is the top upregulated gene in cells resistant to genetic and pharmacologic inhibition of GPX4. In the Cancer Genomic Atlas ChRCC dataset, FSP1 expression is 2-fold higher in ChRCC compared to normal kidney.
Studies on two ChRCC cell lines, UOK276 and RCJ-T2, revealed that while siRNA-mediated inhibition of GPX4 or FSP1 individually did not induce substantial cell death, inhibition of both genes resulted in almost complete cell death. This was rescued by ferrostatin-1 (ferroptosis inhibitor) but not by necrostatin-1 (necroptosis inhibitor) or Z-Vad-FMK (apoptosis inhibitor), confirming ferroptosis. siRNA-mediated GPX4 knockdown combined with FSP1 pharmacologic inhibition (icFSP1 or FSEN1) also induced extensive cell death.
Combining RSL3 with FSEN1 (GPX4 and FSP1 inhibitors, respectively), or IKE with icFSP1 (SLC7A11 and FSP1 inhibitors, respectively), also demonstrated synergy. The ChRCC cell lines showed increased overall sensitivity to these combinations compared to 786-0 (ccRCC-derived) and HeLa cells.
RNA-sequencing demonstrated that siRNA-mediated knockdown of FSP1 in UOK276 cells leads to upregulation of MET and MAPK signaling.
In summary inhibition of FSP1, a glutathione-independent inhibitor of ferroptosis, leads to ferroptosis in ChRCC-derived cells when combined with inhibitors of glutathione homeostasis. Co-targeting these pathways represents a potential therapeutic strategy in ChRCC.
