Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus

Nicolantonio, Federica Di; Arena, Sabrina; Tabernero, Josep; Grosso, Stefano; Molinari, Francesca; Macarulla, Teresa; Russo, Mariangela; Cancelliere, Carlotta; Zecchin, Davide; Mazzucchelli, Luca; Sasazuki, Takehiko; Shirasawa, Senji; Geuna, Massimo; Frattini, Milo; Baselga, José; Gallicchio, Margherita; Biffo, Stefano; Bardelli, Alberto

doi:10.1172/jci37539

Cited by 322 publications

(300 citation statements)

References 39 publications

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“…CT-26 tumour cells harbour an activating mutation in K-Ras, 18 which commonly confers resistance to PI3K/mTORC1/2 inhibition. 19,20 We confirmed this prediction, observing that CT-26 tumours were insensitive to vistusertib when delivered with a regimen that promotes anti-tumour efficacy in sensitive tumour cell lines. 6 .…”

Section: Resultssupporting

confidence: 64%

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

et al. 2018

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ABSTRACTmTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent a net benefit or be contraindicated in the context of immunooncology therapies is less understood. Here, we report that the mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity in combination with anti-CTLA-4 (αCTLA-4), αPD-1 or αPD-L1 immune checkpoint blockade. Combination of vistusertib and immune checkpoint blocking antibodies led to tumour growth inhibition and improved survival of MC-38 or CT-26 pre-clinical syngeneic tumour models, whereas monotherapies were less effective. Underlying these combinatorial effects, vistusertib/immune checkpoint combinations reduced the occurrence of exhausted phenotype tumour infiltrating lymphocytes (TILs), whilst increasing frequencies of activated Th1 polarized T-cells in tumours. Vistusertib alone was shown to promote a Th1 polarizing proinflammatory cytokine profile by innate primary immune cells. Moreover, vistusertib directly enhanced activation of effector T-cell and survival, an effect that was critically dependent on inhibitor dose. Therefore, these data highlight direct, tumour-relevant immune potentiating benefits of mTOR inhibition that complement immune checkpoint blockade. Together, these data provide a clear rationale to investigate such combinations in the clinic.

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Section: Resultssupporting

confidence: 64%

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

et al. 2018

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“…First, we observed an association between K‐Ras mutation and amplification status and resistance to everolimus. Examination of this link was motivated by the findings of a phase II study of single‐agent everolimus in colorectal cancer (Di Nicolantonio et al ., 2010), and response of colon cancer cell lines to the ATP‐competitive mTOR inhibitor PP242 (Ducker et al ., 2014), which demonstrated an association between K‐Ras mutation status and resistance to mTOR inhibitors. Similarly, a study in a large panel of ovarian cancer cell lines identified a link between K‐Ras/BRAF mutation status and resistance to the dual PI3K/mTOR inhibitor, PF‐04691502 (Sheppard et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

“…The objective of this study was to identify biomarkers of everolimus response by in vitro screening of a panel of BTC cell lines. We specifically focussed on mutations in the PI3K pathway and readouts of pathway activity, as well as activation status of K‐Ras, as K‐Ras mutations are predictive of resistance to everolimus in colorectal cancer (Di Nicolantonio et al ., 2010). We demonstrate that cell lines with K‐Ras mutations and/or gene amplifications were associated with resistance to everolimus, even in cell lines harbouring PIK3CA mutations or PTEN loss, suggesting that K‐Ras acts dominantly in this context.…”

Section: Introductionmentioning

confidence: 99%

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

et al. 2017

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Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K‐Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback‐mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP‐competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K‐Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.

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“…Preclinical experiments showed that PIK3CA mutations and PTEN aberrations render tumors sensitive to PI3K pathway inhibitors, whereas simultaneous mutations in the mitogen-activated protein kinase (MAPK) pathway (KRAS, BRAF) can mediate resistance to therapy (35,36). Preliminary clinical data suggested a negative predictive role for tumors harboring KRAS mutations in response to mTORC1 inhibitors (37). Nevertheless, efficacy of mTORC1/2 inhibitors was observed in KRAS/BRAF-mutant colorectal cancer xenograft models, and PI3K/mTOR inhibitors induced tumor regressions in genetically engineered (wt) PIK3CA mouse models (38,39).…”

Section: Discussionmentioning

confidence: 99%

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dienstmann

Serpico

Rodón

et al. 2012

Molecular Cancer Therapeutics

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Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n ¼ 10; or low PTEN, n ¼ 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n ¼ 10; or BRAF mutation, n ¼ 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n ¼ 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n ¼ 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n ¼ 5), and BRAF inhibitor (if BRAF mutation, n ¼ 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease >16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit. Mol Cancer Ther; 11(9); 2062-71. Ó2012 AACR.

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Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus

Cited by 322 publications

References 39 publications

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

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