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|Ref Type||Journal Article|
|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||Acta pharmacologica Sinica|
|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.|
|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||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|
|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|