<i>RICTOR</i> Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors

Cheng, Haiying; Zou, Yiyu; Ross, Jeffrey S.; Wang, Kai; Li, Xuewen; Halmos, Balázs; Ali, Siraj M.; Liu, Huijie; Verma, Amit; Montagna, Cristina; Chachoua, Abraham; Goel, Sanjay; Schwartz, Edward L.; Zhu, Changcheng; Shan, Jidong; Yu, Yiting; Gritsman, Kira; Yelensky, Roman; Lipson, Doron; Otto, Geoff; Hawryluk, Matthew; Stephens, Philip J.; Miller, Vincent A.; Piperdi, Bilal; Pérez-Soler, Román

doi:10.1158/2159-8290.cd-14-0971

Cited by 88 publications

(83 citation statements)

References 27 publications

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“…Following disease progression and failure of immunotherapy, he was enrolled in a phase I clinical trial of MLN0128, another dual mTORC1/2 inhibitor, with ongoing stable disease. Reprinted with permission [43].…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials

Suh¹,

Johnson²,

Albacker³

et al. 2016

The Oncologist

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Background. The National Comprehensive Cancer Network (NCCN) guidelines for patients with metastatic non-small cell lung cancer (NSCLC) recommend testing for EGFR, BRAF, ERBB2, and MET mutations; ALK, ROS1, and RET rearrangements; and MET amplification. We investigated the feasibility and utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) test, in clinical practice. Methods. CGP was performed to a mean coverage depth of 5763 on 6,832 consecutive cases of NSCLC (2012)(2013)(2014)(2015). Genomic alterations (GAs) (point mutations, small indels, copy number changes, and rearrangements) involving EGFR, ALK, BRAF, ERBB2, MET, ROS1, RET, and KRAS were recorded. We also evaluated lung adenocarcinoma (AD) cases without GAs, involving these eight genes. Results. The median age of the patients was 64 years (range: 13-88 years) and 53% were female. Among the patients

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Section: Resultsmentioning

confidence: 99%

Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials

Suh¹,

Johnson²,

Albacker³

et al. 2016

The Oncologist

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“…Like RAC and TRIO, RICTOR has been implicated in several cancers (41–44). A tumor-specific function of RICTOR was demonstrated in studies using knockout mice; RICTOR was shown to be dispensable for normal prostate development but essential for the development of PTEN-loss-induced prostate cancer (41).…”

Section: Discussionmentioning

confidence: 99%

Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma

et al. 2016

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Myxofibrosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profiling of 64 primary high-grade myxofibrosarcomas, we defined an expression signature associated with clinical outcome. The gene most significantly associated with disease-specific death and distant metastasis was ITGA10 (integrin-α10). Functional studies revealed that myxofibrosarcoma cells strongly depended on integrin-α10, whereas normal mesenchymal cells did not. Integrin-α10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had anti-tumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-α10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease.

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“…RICTOR gene amplification and Rictor overexpression was noted in a subset of lung cancer patients with susceptibility to mTORC1/2 dual kinase inhibitors(20). Rictor overexpression was also reported in melanomas(21), glioblastomas (22, 23), gastric cancers(24), and hepatocellular carcinomas(25), supporting a potential role for mTORC2 components in aggressive tumors, and highlighting Rictor/mTORC2 as a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers

et al. 2016

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HER2 overexpression drives Akt signaling and cell survival and HER2-enriched breast tumors have a poor outcome when Akt is upregulated. Akt is activated by phosphorylation at T308 via PI3K and S473 via mTORC2. The importance of PI3K activated Akt signaling is well documented in HER2-amplified breast cancer models, but the significance of mTORC2 activated Akt signaling in this setting remains uncertain. We report here that the mTORC2 obligate cofactor Rictor is enriched in HER2-amplified samples, correlating with increased phosphorylation at S473 on Akt. In invasive breast cancer specimens, Rictor expression was upregulated significantly compared to non-malignant tissues. In a HER2/Neu mouse model of breast cancer, genetic ablation of Rictor decreased cell survival and phosphorylation at S473 on Akt, delaying tumor latency, penetrance and burden. In HER2-amplified cells, exposure to an mTORC1/2 dual kinase inhibitor decreased Akt-dependent cell survival, including in cells resistant to lapatinib where cytotoxicity could be restored. We replicated these findings by silencing Rictor in breast cancer cell lines, but not silencing the mTORC1 cofactor Raptor (RPTOR). Taken together, our findings establish that Rictor/mTORC2 signaling drives Akt-dependent tumor progression in HER2-amplified breast cancers, rationalizing clinical investigation of dual mTORC1/2 kinase inhibitors and development of mTORC2-specific inhibitors for use in this setting.

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RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors

Cited by 88 publications

References 27 publications

Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials

Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials

Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma

Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers

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