Abstract A026: Uncovering genetic regulators of metabolic plasticity and ferroptosis in renal medullary carcinoma

Abstract Renal cell carcinoma (RCC) affects an estimated 400,000 people worldwide per year with over 100,000 deaths reported annually. RCC comprises an array of kidney cancer subtypes differing in incidence, histopathology, genetic and molecular alterations, as well as in clinical outcomes and prognoses. Renal Medullary Carcinoma (RMC) is a subtype that, although rare, is particularly aggressive with limited therapeutic options. Many RCC subtypes exhibit profound metabolic rewiring driven by frequent mutations in genes that regulate major metabolic processes. Metabolic plasticity allows cancer cells to survive and adapt to different environments and metabolic stress conditions, such as nutrient deprivation. Therefore, uncovering the genetic programs that underlie metabolic rewiring may reveal clinically actionable vulnerabilities and dependencies. This could lead to the discovery of novel biomarkers and molecular targets that can be implicated as future therapeutic interventions for this disease. To investigate these mechanisms, we performed functional genomic screens in patient-derived RMC cells to expose genetic dependencies and vulnerabilities under standard and physiologic culture conditions. We applied CHyMErA, a CRISPR-based combinatorial screening platform that is based on co-expression of Cas9 and Cas12a nucleases together with hybrid guide (hg)RNA libraries, enabling ultra-efficient gene perturbation (Aregger et al., 2021; Gonatopoulos-Pournatzis et al., 2020). Genome-wide pooled CRISPR gene knockout screens across a panel of patient-derived RCCs systematically identified genes required for cell survival and proliferation. Notably, we uncovered a striking reliance on pathways that suppress ferroptosis, revealing a targetable vulnerability with therapeutic potential. Ongoing studies aim to explore how these ferroptosis-related and other metabolic dependencies vary across additional RCC models and culture conditions. We are also preforming chemo-genetic screens to map combinatorial targets that sensitize cells to pharmacological inhibitors of the identified targets. In summary, our systematic functional genomics approaches highlight key genetic drivers of metabolic adaptations to different physiological environments in RMC and provide a foundation for developing targeted therapeutic strategies that exploit ferroptosis and metabolic vulnerabilities in this highly lethal cancer subtype. Citation Format: Chelsee Holloway, Josef Horak, Olga Drozdovitch, Youngkyu Jeon, Michael Aregger. NCI, MD. Frederick. Uncovering genetic regulators of metabolic plasticity and ferroptosis in renal medullary carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A026.