The role of RICTOR amplification in targeted therapy and drug resistance

Zhao, Delong; Jiang, Man; Zhang, Xiaochun

doi:10.1186/s10020-020-0146-6

Cited by 22 publications

(16 citation statements)

References 124 publications

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“…Degradation of Rictor by caspase-2 had a similar effect on synaptic pruning as knockdown of Rictor, suggesting that cleavage by caspase-2 renders the protein inactive. Interestingly, Rictor amplification has been noted in a number of different cancer types such as small cell lung cancer, colorectal cancer and esophageal squamous cell carcinoma ( Zhao et al, 2020 ), indicating that cleavage of this putative substrate may play a role outside of neuronal processes to impact cancer progression.…”

Section: Caspase-2 Substratesmentioning

confidence: 99%

Caspase-2 Substrates: To Apoptosis, Cell Cycle Control, and Beyond

Brown-Suedel

Bouchier‐Hayes

2020

Front. Cell Dev. Biol.

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Caspase-2 belongs to the caspase family of proteins responsible for essential cellular functions including apoptosis and inflammation. Uniquely, caspase-2 has been identified as a tumor suppressor, but how it regulates this function is still unknown. For many years, caspase-2 has been considered an “orphan” caspase because, although it is able to induce apoptosis, there is an abundance of conflicting evidence that questions its necessity for apoptosis. Recent evidence supports that caspase-2 has non-apoptotic functions in the cell cycle and protection from genomic instability. It is unclear how caspase-2 regulates these opposing functions, which has made the mechanism of tumor suppression by caspase-2 difficult to determine. As a protease, caspase-2 likely exerts its functions by proteolytic cleavage of cellular substrates. This review highlights the known substrates of caspase-2 with a special focus on their functional relevance to caspase-2’s role as a tumor suppressor.

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Section: Caspase-2 Substratesmentioning

confidence: 99%

Caspase-2 Substrates: To Apoptosis, Cell Cycle Control, and Beyond

Brown-Suedel

Bouchier‐Hayes

2020

Front. Cell Dev. Biol.

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“…Furthermore, CDK4/6 amplifications have been associated with longer PFS in hormone receptor-positive, HER2-negative metastatic breast cancer patients treated with CDK4/6 inhibitors [15]. Finally, RICTOR amplification has been proposed as a mechanism of resistance to TKIs and potential therapeutic target in this setting [16].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Copy Number Variations in Solid Tumors Using a Next Generation Sequencing Custom Panel

Vives-Usano

Peláez

Lladó

et al. 2021

JMP

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Somatic copy number variations (CNV; i.e., amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies. Although FISH is still considered the gold standard for CNV detection, the increasing number of potentially druggable amplifications to be assessed makes a gene-by-gene approach time- and tissue-consuming. Here we investigated the potential of next generation sequencing (NGS) custom panels to simultaneously determine CNVs across FFPE solid tumor samples. DNA was purified from cell lines and FFPE samples and analyzed by NGS sequencing using a 20-gene custom panel in the GeneReader Platform®. CNVs were identified using an in-house algorithm based on the UMI read coverage. Retrospective validation of in-house algorithm to identify CNVs showed 97.1% concordance rate with the NGS custom panel. The prospective analysis was performed in a cohort of 243 FFPE samples from patients arriving at our hospital, which included 74 NSCLC tumors, 148 CRC tumors, and 21 other tumors. Of them, 33% presented CNVs by NGS and in 14 cases (5.9%) the CNV was the only alteration detected. We have identified CNV alterations in about one-third of our cohort, including FGFR1, CDK6, CDK4, EGFR, MET, ERBB2, BRAF, or KRAS. Our work highlights the need to include CNV testing as a part of routine NGS analysis in order to uncover clinically relevant gene amplifications that can guide the selection of therapies.

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“…Furthermore, the ILK/RICTOR complex is known to phosphorylate Akt and induce EMT [ 23 , 46 ]. RICTOR is speculated to be involved in the development of drug resistance in tyrosine kinase inhibitors therapy [ 47 ]. Perhaps the mTORC2 activation observed as an increase in S2481 phosphorylation is the effect of RICTOR’s release from the ILK complex after silencing in 1205Lu cells, or the activation of mTORC2 is a feedback mechanism to enhance cell survival after CQ treatment.…”

Section: Discussionmentioning

confidence: 99%

Inhibition Effect of Chloroquine and Integrin-Linked Kinase Knockdown on Translation in Melanoma Cells

Gil

Laidler

Zarzycka

et al. 2021

IJMS

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The twofold role of autophagy in cancer is often the therapeutic target. Numerous regulatory pathways are shared between autophagy and other molecular processes needed in tumorigenesis, such as translation or survival signaling. Thus, we have assumed that ILK knockdown should promote autophagy, and used together with chloroquine, an autophagy inhibitor, it could generate a better anticancer effect by dysregulation of common signaling pathways. Expression at the protein level was analyzed using Western Blot; siRNA transfection was done for ILK. Analysis of cell signaling pathways was monitored with phospho-specific antibodies. Melanoma cell proliferation was assessed with the crystal violet test, and migration was evaluated by scratch wound healing assays. Autophagy was monitored by the accumulation of its marker, LC3-II. Our data show that ILK knockdown by siRNA suppresses melanoma cell growth by inducing autophagy through AMPK activation, and simultaneously initiates apoptosis. We demonstrated that combinatorial treatment of melanoma cells with CQ and siILK has a stronger antitumor effect than monotherapy with either of these. It generates the synergistic antitumor effects by the decrease of translation of both global and oncogenic proteins synthesis. In our work, we point to the crosstalk between translation and autophagy regulation.

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The role of RICTOR amplification in targeted therapy and drug resistance

Cited by 22 publications

References 124 publications

Caspase-2 Substrates: To Apoptosis, Cell Cycle Control, and Beyond

Caspase-2 Substrates: To Apoptosis, Cell Cycle Control, and Beyond

Analysis of Copy Number Variations in Solid Tumors Using a Next Generation Sequencing Custom Panel

Inhibition Effect of Chloroquine and Integrin-Linked Kinase Knockdown on Translation in Melanoma Cells

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