Reference Detail

Ref Type

Journal Article

PMID

(35165399)

Authors

Liu XL, Zhang GM, Huang SS, Shi WH, Ye LX, Ren ZL, Zhang JJ, Liu SW, Yu L, Li YL

Title

PTEN loss confers sensitivity to rapalogs in clear cell renal cell carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Acta pharmacologica Sinica	43	9	2022 Sep	2397-2409	Acta Pharmacol Sin

URL

Abstract Text

Rapalogs (everolimus and temsirolimus) are allosteric mTORC1 inhibitors and approved agents for advanced clear cell renal cell carcinoma (ccRCC), although only a subset of patients derive clinical benefit. Progress in genomic characterization has made it possible to generate comprehensive profiles of genetic alterations in ccRCC; however, the correlations between recurrent somatic mutations and rapalog efficacy remain unclear. Here, we demonstrate by using multiple patient-derived ccRCC cell lines that compared to PTEN-proficient cells, PTEN-deficient cells exhibit hypersensitivity to rapalogs. Rapalogs inhibit cell proliferation by inducing G0/G1 arrest without inducing apoptosis in PTEN-deficient ccRCC cell lines. Using isogenic cell lines generated by CRISPR/Cas9, we validate the correlation between PTEN loss and rapalog hypersensitivity. In contrast, deletion of VHL or chromatin-modifying genes (PBRM1, SETD2, BAP1, or KDM5C) fails to influence the cellular response to rapalogs. Our mechanistic study shows that ectopic expression of an activating mTOR mutant (C1483F) antagonizes PTEN-induced cell growth inhibition, while introduction of a resistant mTOR mutant (A2034V) enables PTEN-deficient ccRCC cells to escape the growth inhibitory effect of rapalogs, suggesting that PTEN loss generates vulnerability to mTOR inhibition. PTEN-deficient ccRCC cells are more sensitive to the inhibitory effects of temsirolimus on cell migration and tumor growth in zebrafish and xenograft mice, respectively. Of note, PTEN protein loss as detected by immunohistochemistry is much more frequent than mutations in the PTEN gene in ccRCC patients. Our study suggests that PTEN loss correlates with rapalog sensitivity and could be used as a marker for ccRCC patient selection for rapalog therapy.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN loss	clear cell renal cell carcinoma	sensitive	Temsirolimus	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Torisel (temsirolimus) inhibited cell proliferation and induced cell cycle arrest in PTEN-deficient clear cell renal carcinoma cell lines in culture and inhibited tumor growth in a cell line xenograft model (PMID: 35165399).	35165399
PTEN loss	clear cell renal cell carcinoma	sensitive	Everolimus	Preclinical - Cell culture	Actionable	In a preclinical study, Afinitor (everolimus) inhibited cell proliferation in PTEN-deficient clear cell renal carcinoma cell lines in culture (PMID: 35165399).	35165399