mTOR Pathway Mutations and Response to Rapalogs in RCC—Letter

Roldán-Romero, Juan María; Rodriguez-Moreno, Juan Francisco; García-Donás, Jesús; Rodríguez‐Antona, Cristina

doi:10.1158/1078-0432.ccr-17-1280

Cited by 4 publications

(5 citation statements)

References 4 publications

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“…The characteristics of the patients are summarized in Table . Mutational analysis results were obtained in 87 patients (results from 45 cases were previously described). In 14 patients, there were at least two different tumor blocks, corresponding to primary and/or metastasis lesions, available for the analysis.…”

Section: Methodsmentioning

confidence: 99%

PTEN expression and mutations in TSC1, TSC2 and MTOR are associated with response to rapalogs in patients with renal cell carcinoma

Roldán-Romero

Beuselinck

Santos

et al. 2019

Intl Journal of Cancer

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The mammalian target of rapamycin (mTOR) pathway inhibitors are key drugs for the treatment of many tumor types, however, there are no predictive biomarkers in clinical use. Here, we performed a molecular and immunohistochemical characterization of key mTOR pathway components in a series of 105 renal cell carcinoma patients treated with rapalogs, aimed at identifying markers of treatment response. Mutational analysis in MTOR, TSC1 and TSC2 was performed through targeted next‐generation sequencing (NGS), and immunohistochemistry (IHC) was performed for PTEN, pAKT, pS6K1, pS6 and p21. Among patients with NGS data, 11 of 87 (13%) had mTOR pathway mutations (8 in MTOR, 1 in TSC1 and 2 in TSC2). When comparing the molecular data to the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (odds ratio [OR] = 0.08, 95% confidence interval [CI] = 0.008–0.79, p = 0.030 univariate; p = 0.038 multivariable). Regarding IHC, negative PTEN staining was detected in 58% of the tumors, and it was more frequent in rapalog responder patients (OR = 0.24, 95% CI = 0.065–0.86, p = 0.029 univariate; p = 0.029 multivariable). Mutations and PTEN IHC were not mutually exclusive events and its combination improved response prediction (OR = 0.16, 95% CI = 0.04–0.62, p = 0.008 univariate; p = 0.013 multivariable). The staining of other proteins did not show and association with response and no association with PFS was observed in unselected patients. In conclusion, our findings suggest that mTOR pathway mutations, negative PTEN IHC and their combination are potential markers of rapalog response.

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Section: Methodsmentioning

confidence: 99%

PTEN expression and mutations in TSC1, TSC2 and MTOR are associated with response to rapalogs in patients with renal cell carcinoma

Roldán-Romero

Beuselinck

Santos

et al. 2019

Intl Journal of Cancer

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“…Epigenetic mechanisms or direct effects of rapalogs on the tumor microenvironment might be at play. Nevertheless, mutations in tuberous sclerosis proteins TSC1 or TSC2, close upstream regulators of mTORC1, and mTOR are more common among rapalog responders (Kwiatkowski et al, 2016;Roldan-Romero et al, 2017). More promisingly, loss of PTEN expression, and not loss-offunction mutations, has recently been associated with everolimus therapeutic response (Voss et al, 2019;Roldan-Romero et al, 2020).…”

Section: Activation Of Mechanistic Target Of Rapamycin In Renal Cell mentioning

confidence: 99%

Mechanistic Target of Rapamycin Inhibitors in Renal Cell Carcinoma: Potential, Limitations, and Perspectives

Faes

Demartines

Dormond

2021

Front. Cell Dev. Biol.

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Several elements highlight the importance of the mechanistic target of rapamycin (mTOR) in the biology of renal cell carcinoma (RCC). mTOR signaling pathway is indeed frequently activated in RCC, inducing cancer cell proliferation and survival. In addition, mTOR promotes tumor angiogenesis and regulates the expression of hypoxia-inducible factors that play an important role in a subset of RCC. Despite mTOR protumorigenic effects, mTOR inhibitors have failed to provide long-lasting anticancer benefits in RCC patients, highlighting the need to readdress their role in the treatment of RCC. This review aims to present the rationale and limitations of targeting mTOR in RCC. Future roles of mTOR inhibitors in the treatment of RCC are also discussed, in particular in the context of immunotherapies.

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“…In cancer, the hyperactivation of mTOR signaling contributes to tumor initiation and progression; as such, two small molecule inhibitors that target this pathway, the rapalogs temsirolimus and everolimus, are approved for the treatment of several tumors, including advanced renal cell carcinoma. Mutations in key components of the mTOR pathway ( MTOR , TSC1 and TSC2 ) 1 are associated with increased rapalog sensitivity, 2‐7 yet this only represents a small proportion of sensitive tumors 8‐11 . This means that mutations in other genes could provide information concerning the sensitivity of these small molecule inhibitors for certain tumor types.…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in key components of the mTOR pathway (MTOR, TSC1 and TSC2) 1 are associated with increased rapalog sensitivity, [2][3][4][5][6][7] yet this only represents a small proportion of sensitive tumors. [8][9][10][11] This means that mutations in other genes could provide information concerning the sensitivity of these small molecule inhibitors for certain tumor types.…”

Section: Introductionmentioning

confidence: 99%

Deubiquitinase USP9X loss sensitizes renal cancer cells to mTOR inhibition

Roldán-Romero

Valdivia

Santos

et al. 2023

Intl Journal of Cancer

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Mammalian target of rapamycin (mTOR) is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of the mTOR pathway promotes tumor growth and metastasis, and can also promote tumor resistance to chemotherapy and cancer drugs; this makes mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer; however, the mechanisms underlying drug sensitivity remain poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity revealed that all three patients shared somatic mutations in the deubiquitinase gene USP9X. The clonal characteristics of the mutations, which were amassed by studying multiple patients' primary and metastatic samples from various years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X-depleted HeLa and renal cancer 786-O cells, along with the pharmacological inhibition of USP9X, confirmed that this protein plays a role in patients' sensitivity to mTOR inhibitors. USP9X was not found to exert a direct effect on mTORC1, but subsequent ubiquitylome analyses identified p62 as a direct USP9X target. Increased p62 ubiquitination and the augmented rapamycin effect upon bortezomib treatment, together with the results of p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X-depleted cells can have a synergistic effect with mTOR inhibitors. In summary, we show that USP9X constitutes a potential novel Abbreviations: chRCC, chromophobe renal cell carcinoma; DAPI, 4,6-diamidino-2-phenylindole; IHC, immunohistochemistry; indels, small insertions or deletions; KO, knockout; mTOR, mammalian target of rapamycin; SNVs, single nucleotide variants; WES, whole exome sequencing.

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mTOR Pathway Mutations and Response to Rapalogs in RCC—Letter

Cited by 4 publications

References 4 publications

PTEN expression and mutations in TSC1, TSC2 and MTOR are associated with response to rapalogs in patients with renal cell carcinoma

PTEN expression and mutations in TSC1, TSC2 and MTOR are associated with response to rapalogs in patients with renal cell carcinoma

Mechanistic Target of Rapamycin Inhibitors in Renal Cell Carcinoma: Potential, Limitations, and Perspectives

Deubiquitinase USP9X loss sensitizes renal cancer cells to mTOR inhibition

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