Open AccessSensitivity ofVHLmutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway
Author(s) -
Laura Stransky,
Sean M. Vigeant,
Bofu Huang,
Destiny West,
Thomas Denize,
Emily Walton,
Sabina Signoretti,
William G. Kaelin
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2120403119
Subject(s) - cancer research , clear cell renal cell carcinoma , biology , tumor suppressor gene , hypoxia inducible factors , cancer , carcinogenesis , renal cell carcinoma , medicine , genetics , gene , oncology
Significance VHL tumor suppressor gene inactivation is a hallmark of clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and promotes tumor growth by stabilizing the hypoxia-inducible factor 2 (HIF2) transcription factor. HIF2 inhibitors appear to be helpful for some, but not all, ccRCC patients in clinical trials. Previous preclinical and clinical data suggested that only ccRCCs that can activate the p53 tumor suppressor in response to DNA damage would respond to HIF2 inhibitors. Here, we show that an intact p53 pathway is neither necessary nor sufficient for the sensitivity of ccRCCs to HIF2 inhibitors, suggesting that it would be premature to use p53 status to determine which ccRCC patients should be treated with a HIF2 inhibitor.