Biology subjects

Chakraborty, A. A.

Publications and source records attributed to Chakraborty, A. A..

3 recordsLinked to original sources

bioRxiv2025

BCL-XL Dependence is a Subtype Agnostic Actionable Feature of Difficult-to-Treat Kidney Cancers

The BCL-XL anti-apoptotic protein is a clear cell Renal Cell Carcinoma (ccRCC) dependency; however, the mechanism of this dependence and its relevance in other aggressive kidney cancer contexts, including metastatic and/or rare RCC subtypes [e.g., Fumarate Hydratase (FH)-deficient and sarcomatoid RCCs], is unknown. Computational predictions, using a machine learning model trained on the human RCC TCGA dataset, and cell-based validations, confirmed BCL-XL dependence in all RCC subtypes. Remarkably, cell state changes, anoikis programs, inflammatory state, and metabolic perturbations (e.g., fumarate production in FH-deficient RCCs) independently conferred increased BCL-XL dependence. Correlation studies revealed that increased AMPK isoform 2 (PRKAA2) expression is a kidney-specific biomarker of BCL-XL dependence. Indeed, pharmacological AMPK activation sensitized RCCs to BCL-XL blockade. Finally, using functional studies, we developed a multivariate model that accurately predicted BCL-XL dependence in RCC. Our studies offer biomarkers for patient stratification and credential BCL-XL as a subtype agnostic vulnerability in difficult-to-treat RCCs.

cancer biology↗

bioRxiv2025

Mechanism and Structure-Guided Optimization of SLC1A1/EAAT3-Selective Inhibitors in Kidney Cancer

Renal Cell Carcinomas (RCCs) depend metabolically on the trimeric sodium-coupled aspartate and glutamate transporter, SLC1A1/EAAT3; however, pharmacologically targeting SLC1A1 is challenging. We determined a cryo-EM structure of human SLC1A1 bound to compound 3e, a recently described SLC1A1-selective bicyclic imidazo[1,211]pyridine-3-amine (BIA) inhibitor. 3e binds a membrane-embedded allosteric pocket accessible only in the apo state, when SLC1A1 is unbound to substrate and sodium, and likely prevents sodium and substrate binding. Moreover, by wedging between the trimerization domain and the substrate-binding transport domain, alongside a cholesterol moiety from the lipid bilayer, 3e blocks SLC1A1s elevator-like movements that are essential for transport. Mutations in this binding pocket abolish 3e interaction and counteract 3es cytotoxicity in RCC cells, confirming on-target activity and explaining SLC1A1 selectivity. A structure-guided medicinal chemistry effort yielded two new SLC1A1-selective BIA derivatives, PBJ1 and PBJ2, with enhanced cytotoxicity resulting from the inhibition of SLC1A1-dependent aspartate, glutamate, and cysteine metabolism.

cancer biology↗

bioRxiv2023

The SLC1A1/EAAT3 Dicarboxylic Amino Acid Transporter is an Epigenetically Dysregulated Nutrient Carrier that Sustains Oncogenic Metabolic Programs

Inactivation of pVHL tumor suppressor in clear cell Renal Cell Carcinoma (ccRCC) increases the abundance of Histone H3 lysine 27 acetylation (H3K27ac). We hypothesized that H3K27ac, a marker of transcriptional activation, drives the expression of critical oncogenes in ccRCC. Using H3K27ac ChIP-Seq; RNA-Seq; an in vivo positive selection screen; cell-based functional studies; and clinical validations; here, we report the identification of the SLC1A1/EAAT3 aspartate (Asp) and glutamate (Glu) transporter as a ccRCC oncogene. pVHL loss promotes SLC1A1 expression in a HIF-independent manner. Importantly, SLC1A1 inactivation depletes Asp/Glu-derived metabolites, impedes ccRCC growth both in vitro and in vivo, and sensitizes ccRCCs to metabolic therapeutics (e.g., glutaminase blockers). Finally, in human ccRCC biospecimens, higher SLC1A1 expression is associated with metastatic disease and clusters with elevated expression of other solute carriers, but not HIF/Hypoxia pathways. Altogether, our studies identify a HIF-independent metabolic hub in ccRCC and credential SLC1A1 as an actionable ccRCC oncogene. STATEMENT OF SIGNIFICANCETargeting chronic HIF activation underlies many therapeutic strategies in ccRCC; but, unfortunately, is not curative. SLC1A1, instead, represents a HIF-independent ccRCC dependency, which is targetable alone and together with other antimetabolites, such as glutaminase inhibitors. These observations identify an actionable metabolic program that functions independent of HIF in ccRCC.

cancer biology↗