ABL1 activation in FH-deficient cancers confers protection from fumarate-induced metabolic stress.
Major finding: ABL1 activation in FH-deficient cancers confers protection from fumarate-induced metabolic stress.
Mechanism: ABL1 inhibition dampens glycolytic signaling and NRF2-mediated oxidative stress responses.
Impact: ABL1 inhibitors may have clinical success in glycolytic FH-deficient tumors with oxidative stress.
Hereditary leiomyomatosis and renal cell carcinomas (HLRCC) harboring germline mutations in the tricarboxylic acid cycle gene fumarate hydratase (FH) exhibit intracellular accumulation of fumarate, resulting in a metabolic adaptation characterized by high glycolytic activity and unbalanced redox homeostasis. Currently, there is no effective therapy for aggressive FH-deficient kidney cancers, prompting Sourbier and colleagues to perform an unbiased drug screen to identify potential therapeutic compounds that are cytotoxic to HLRCC-derived cells. Treatment of HLRCC cells with a panel of 17 drugs revealed high sensitivity to the tyrosine kinase inhibitor vandetanib, which was reversed upon restored expression of wild-type FH. Vandetanib treatment also decreased invasiveness and mTOR-mediated translation of hypoxia-inducible factor 1α (HIF1α) by inhibiting the upstream regulatory kinase ABL1. Constitutive ABL1 activation was observed across HLRCC tumor samples and cell lines, and ABL1 kinase activity was required to rescue HLRCC cell proliferation following genetic suppression of ABL1. In line with ABL1′s role in regulating HIF1α, vandetanib decreased glucose transporter expression, glucose uptake, and lactate secretion in vitro, and suppressed pyruvate conversion to lactate and xenograft tumor growth in vivo, reinforcing the notion that ABL1 blockade inhibits aerobic glycolysis. Mechanistically, ABL1 activation in response to excess fumarate was dependent on reactive oxygen species (ROS) and neutralized oxidative stress by promoting the nuclear localization and transcriptional activity of nuclear factor, erythroid 2–like 2 (NRF2), which regulates the antioxidant response. Importantly, combined treatment with metformin, an activator of AMP-activated kinase that promotes sirtuin 1–mediated inactivation of NRF2, and vandetanib additively inhibited NRF2 and induced prolonged regression of HLRCC xenograft tumors. Together, these results provide a rationale for therapeutically exploiting ABL1 and ROS defense pathways in FH-deficient cancers.