Differential Efficacy of Bevacizumab and Erlotinib in Preclinical Models of Renal Medullary Carcinoma and Fumarate Hydratase–Deficient Renal Cell Carcinoma

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Abstract
Renal medullary carcinoma (RMC) and fumarate hydratase (FH)–deficient renal cell carcinoma (RCC) are rare and highly aggressive cancers. Although the combination of VEGF inhibition by bevacizumab and EGFR inhibition by erlotinib is clinically used for both diseases, the differential effect of each component has not been investigated. Transcriptomic profiling revealed that RMC and FH-deficient tumor tissues demonstrate increased EGFR but not VEGF expression compared with adjacent normal kidney. Subsequent in vitro studies revealed that RMC and FH-deficient cell lines are sensitive to erlotinib treatment, whereas clear-cell RCC cell lines are resistant. We developed patient-derived xenograft (PDX) models of tumors exposed to first-line therapies to represent treatment-experienced RMC and FH-deficient RCC models. These models were then used to determine tumor growth response to angiogenesis inhibition by bevacizumab alone or in combination with erlotinib. The FH-deficient RCC PDX model responded to either bevacizumab or erlotinib alone or in combination, whereas the RMC PDX model responded only to erlotinib, consistent with clinical and preclinical data suggesting that RMC is refractory to angiogenesis inhibition. Statistically higher expression of EGFR was observed in the RMC PDX model compared with the FH-deficient model, whereas higher phosphorylated tyrosine-416 SRC expression was observed in the FH-deficient PDX model compared with the RMC model. Our preclinical data suggest that EGFR signaling differentially modulates tumor growth in RMC and FH-deficient RCC and that angiogenesis inhibition is a valid target in FH-deficient RCC but not RMC.
Funding Information
  • National Cancer Institute (P30 CA016672)
  • Cancer Prevention and Research Institute of Texas (RP230271)
  • Cancer Prevention and Research Institute of Texas (RP230271)
  • Cancer Prevention and Research Institute of Texas (RP230217)
  • Cancer Prevention and Research Institute of Texas (RP230217)
  • Cancer Prevention and Research Institute of Texas (RP230217)
  • Cancer Prevention and Research Institute of Texas (RP230217)
  • National Institutes of Health (CA096300, CA096297)
  • MD Anderson Partnership for Careers in Cancer Science Program
  • Erickson Kidney Cancer Foundation
  • Eickson Kidney Cancer Foundation
  • National Institutes of Health (R37CA288448)
  • Andrew Sabin Family Foundation
  • Gateway for Cancer Research
  • U.S. Department of War (KC200096P1)
  • U.S. Department of War (KC210213)
  • U.S. Department of War (KC210213)
  • Kidney Cancer Association
  • V Foundation for Cancer Research
  • University of Texas MD Anderson Cancer Center
  • Finneran Family Endowment
  • University of Texas MD Anderson Cancer Center
  • Chrs "CJ" Johnson Foundation
  • Mike and Mary Allen

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