Zacharias Niki M, Ozambela Manuel, Karki Menuka, He Rong, Chauhan Pankaj K, Pesquera Pedro I, Hernandez Gonzalez Andres E, Ochoa Oscar, Pieretti Alberto, Chen Huiqin, De La Cerda Carolyn, Yu Zhiyuan, Grover Abha, Hicks-Peña Samantha, Fowlkes Natalie W, Wang Lei, Maity Tapati, Rao Priya, Genovese Giannicola, Tannir Nizar M, Karam Jose A, Msaouel Pavlos
The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Baptist Health Miami Cancer Institute, Miami, FL, United States.
Mol Cancer Ther. 2025 Jul 2. doi: 10.1158/1535-7163.MCT-24-0703.
Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare and highly aggressive cancers. Although the combination of vascular endothelial growth factor (VEGF) inhibition by bevacizumab and epidermal growth factor receptor (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 while the RMC PDX 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 to the FH-deficient model; while higher phosphorylated tyrosine-416 SRC expression was observed in FH-deficient PDX model compared to 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.
肾髓质癌（RMC）和富马酸水合酶（FH）缺陷型肾细胞癌（RCC）是罕见且侵袭性很强的癌症。尽管贝伐单抗抑制血管内皮生长因子（VEGF）与厄洛替尼抑制表皮生长因子受体（EGFR）的联合疗法在临床上用于这两种疾病，但尚未对每种成分的不同作用进行研究。转录组分析显示，与相邻正常肾组织相比，RMC和FH缺陷型肿瘤组织中EGFR表达增加，但VEGF表达未增加。随后的体外研究表明，RMC和FH缺陷型细胞系对厄洛替尼治疗敏感，而透明细胞RCC细胞系具有抗性。我们建立了接受一线治疗的肿瘤的患者来源异种移植（PDX）模型，以代表有治疗经验的RMC和FH缺陷型RCC模型。然后使用这些模型来确定单独使用贝伐单抗或与厄洛替尼联合使用时肿瘤对血管生成抑制的生长反应。FH缺陷型RCC PDX模型对单独使用贝伐单抗或厄洛替尼或两者联合使用均有反应，而RMC PDX仅对厄洛替尼有反应，这与临床和临床前数据一致，表明RMC对血管生成抑制具有抗性。与FH缺陷型模型相比，RMC PDX模型中EGFR的表达在统计学上更高；而与RMC模型相比，FH缺陷型PDX模型中磷酸化酪氨酸-416 SRC的表达更高。我们的临床前数据表明，EGFR信号通路对RMC和FH缺陷型RCC中的肿瘤生长有不同的调节作用，血管生成抑制是FH缺陷型RCC而非RMC的有效靶点。
