Targeting ferroptosis pathway vulnerability in small cell lung cancer (SCLC)

• Applicant: Professorin Dr. Silvia von Karstedt
• Subject Area: Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432038712

Small cell lung cancer (SCLC) is amongst the most aggressive forms of lung cancer with a 5-year survival rate of only 5%. Despite this dismal prognosis, SCLC is initially highly sensitivity to chemotherapy. However, almost invariably, chemotherapy resistance develops very quickly after this initial response. Large-scale sequencing efforts have revealed that, unlike non-small cell lung cancer (NSCLC), SCLC presents with an almost uniform lack of driver mutations hampering the use of targeted therapy. Recently, is was uncovered that chemo-naïve SCLC cancer tissue is characterised by bi-allelic loss of p53 and Rb. Therefore, the intrinsic apoptosis pathway is already disabled in these tumours before treatment highlighting the need to understand alternative means to kill SCLC. Here, we have systematically RNA-profiled expression of cell death pathway components in human SCLC in order to understand which cell death pathways are open to be triggered by therapy. We identify that whilst components required for the execution of extrinsic apoptosis and necroptosis are strongly downregulated in SCLC suggesting their negative selection, key components involved in preventing aberrant ferroptosis, a recently discovered type of regulated necrosis, are highly expressed. Importantly, interfering with activity of the ferroptosis pathway components xCT and GPX4 induced lipid peroxidation and showed strong killing activity in a subset of human and murine chemo-naïve SCLC cells which could be reversed by the antioxidant Ferrostatin-1. Therefore, therapeutic induction of ferroptosis might represent an opportunity to efficiently induce cell death in SCLC. However, determinants of response and resistance need clarification. Therefore, to achieve an in depth and systemic understanding of this novel cell death mode in SCLC, we plan to fulfill the following three aims: i) Identify pathways regulating differential ferroptosis sensitivity in human and murine SCLC, ii) Target ferroptosis pathway vulnerabilities in xenografts and patient-derived xenografts and iii) to determine the in-vivo role of GPX4 in a genetically engineered mouse model (GEMM) for SCLC. With completion of these research aims we anticipate to provide novel therapeutic opportunities for the treatment of SCLC.

• DFG Programme: Research Grants