TY - JOUR
T1 - Altered Regulation of HIF-1α in Naive- and Drug-Resistant EGFR-Mutant NSCLC
T2 - Implications for a Vascular Endothelial Growth Factor-Dependent Phenotype
AU - Nilsson, Monique B.
AU - Robichaux, Jacqulyne
AU - Herynk, Matthew H.
AU - Cascone, Tina
AU - Le, Xiuning
AU - Elamin, Yasir
AU - Patel, Sonia
AU - Zhang, Fahao
AU - Xu, Li
AU - Hu, Limei
AU - Diao, Lixia
AU - Shen, Li
AU - He, Junqin
AU - Yu, Xiaoxing
AU - Nikolinakos, Petros
AU - Saintigny, Pierre
AU - Fang, Bingliang
AU - Girard, Luc
AU - Wang, Jing
AU - Minna, John D.
AU - Wistuba, Ignacio I.
AU - Heymach, John V.
N1 - Publisher Copyright:
© 2020
PY - 2021/3
Y1 - 2021/3
N2 - Introduction: The treatment of patients with EGFR-mutant NSCLC with vascular endothelial growth factor (VEGF) inhibitors in combination with EGFR inhibitors provides a greater benefit than EGFR inhibition alone, suggesting that EGFR mutation status may define a patient subgroup with greater benefit from VEGF blockade. The mechanisms driving this potentially enhanced VEGF dependence are unknown. Methods: We analyzed the effect of EGFR inhibition on VEGF and HIF-1α in NSCLC models in vitro and in vivo. We determined the efficacy of VEGF inhibition in xenografts and analyzed the impact of acquired EGFR inhibitor resistance on VEGF and HIF-1α. Results: NSCLC cells with EGFR-activating mutations exhibited altered regulation of VEGF compared with EGFR wild-type cells. In EGFR-mutant cells, EGFR, not hypoxia, was the dominant regulator of HIF-1α and VEGF. NSCLC tumor models bearing classical or exon 20 EGFR mutations were more sensitive to VEGF inhibition than EGFR wild-type tumors, and a combination of VEGF and EGFR inhibition delayed tumor progression. In models of acquired EGFR inhibitor resistance, whereas VEGF remained overexpressed, the hypoxia-independent expression of HIF-1α was delinked from EGFR signaling, and EGFR inhibition no longer diminished HIF-1α or VEGF expression. Conclusions: In EGFR-mutant NSCLC, EGFR signaling is the dominant regulator of HIF-1α and VEGF in a hypoxia-independent manner, hijacking an important cellular response regulating tumor aggressiveness. Cells with acquired EGFR inhibitor resistance retained elevated expression of HIF-1α and VEGF, and the pathways were no longer EGFR-regulated. This supports VEGF targeting in EGFR-mutant tumors in the EGFR inhibitor–naive and refractory settings.
AB - Introduction: The treatment of patients with EGFR-mutant NSCLC with vascular endothelial growth factor (VEGF) inhibitors in combination with EGFR inhibitors provides a greater benefit than EGFR inhibition alone, suggesting that EGFR mutation status may define a patient subgroup with greater benefit from VEGF blockade. The mechanisms driving this potentially enhanced VEGF dependence are unknown. Methods: We analyzed the effect of EGFR inhibition on VEGF and HIF-1α in NSCLC models in vitro and in vivo. We determined the efficacy of VEGF inhibition in xenografts and analyzed the impact of acquired EGFR inhibitor resistance on VEGF and HIF-1α. Results: NSCLC cells with EGFR-activating mutations exhibited altered regulation of VEGF compared with EGFR wild-type cells. In EGFR-mutant cells, EGFR, not hypoxia, was the dominant regulator of HIF-1α and VEGF. NSCLC tumor models bearing classical or exon 20 EGFR mutations were more sensitive to VEGF inhibition than EGFR wild-type tumors, and a combination of VEGF and EGFR inhibition delayed tumor progression. In models of acquired EGFR inhibitor resistance, whereas VEGF remained overexpressed, the hypoxia-independent expression of HIF-1α was delinked from EGFR signaling, and EGFR inhibition no longer diminished HIF-1α or VEGF expression. Conclusions: In EGFR-mutant NSCLC, EGFR signaling is the dominant regulator of HIF-1α and VEGF in a hypoxia-independent manner, hijacking an important cellular response regulating tumor aggressiveness. Cells with acquired EGFR inhibitor resistance retained elevated expression of HIF-1α and VEGF, and the pathways were no longer EGFR-regulated. This supports VEGF targeting in EGFR-mutant tumors in the EGFR inhibitor–naive and refractory settings.
KW - Epidermal growth factor receptor
KW - Hypoxia-inducible factor
KW - Non–small cell lung cancer
KW - Vascular endothelial growth factor
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U2 - 10.1016/j.jtho.2020.11.022
DO - 10.1016/j.jtho.2020.11.022
M3 - Article
C2 - 33309987
AN - SCOPUS:85099290471
SN - 1556-0864
VL - 16
SP - 439
EP - 451
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 3
ER -