AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity

Chandarlapaty, Sarat; Sawai, Ayana; Scaltriti, Maurizio; Rodrik-Outmezguine, Vanessa; Grbovic-Huezo, Olivera; Serra, Violeta; Majumder, Pradip K.; Baselga, José; Rosen, Neal

doi:10.1016/j.ccr.2010.10.031

Cited by 863 publications

(916 citation statements)

References 36 publications

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“…Overactivation of AKT was expected, as PTEN is a negative regulator of the PI3K-AKT pathway, whereas the latter might be explained by the extensive mTOR-negative feedback loops and cross-talks between the PI3K and the RAS-mediated MAPK pathways that have been well documented among the signaling networks driving tumor progression. 21,22 Finally, we have investigated the effect of PI3K/ mTOR inhibition, alone or in combination with imatinib, on PTENsi GIST cell lines.…”

Section: Discussionmentioning

confidence: 99%

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

et al. 2014

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Insufficiency of phosphatase and tensin homolog (PTEN) occurs in numerous tumor types and has been implicated as a resistance mechanism to receptor tyrosine kinase-targeted therapies in human cancer. In this study, we have performed a comprehensive molecular and immunohistochemical characterization of PTEN in 58 imatinib-naı¨ve and 54 imatinib-treated gastrointestinal stromal tumors (GISTs). The findings were correlated with clinicopathological data. At the genomic level, PTEN was affected mainly by mono-allelic loss, which was significantly less frequent in imatinib-naı¨ve vs imatinib-resistant tumors (9% vs 39%, Po0.001). Neither PTEN mutations nor PTEN promoter hyper-methylation were found. By immunohistochemistry, PTEN depletion was clearly related to GIST progression. Low PTEN protein expression was common (50%) and often paralleled with total immunonegativity in imatinib-resistant tumors. The abnormal PTEN protein expression correlated with PTEN loss at the genomic level (P ¼ 0.001). In addition, the effect of small interfering RNA (siRNA) PTEN knockdown on KIT signaling was examined in GIST-T1 and GIST430 cell lines, in the absence or presence of a dual PI3K/mTOR inhibitor NVP-BEZ235, alone or in combination with imatinib. In both cell lines, siRNA silencing of PTEN resulted in the substantial upregulation of PI3K-AKT and MAPK pathways. The MAPK hyperactivation was further potentiated by NVP-BEZ235 in the imatinib-sensitive GIST-T1 cells; yet, this effect was counteracted efficiently by combined treatment. In the imatinib-resistant GIST430 cells, neither NVP-BEZ235 alone or in combination with imatinib yielded sufficient inhibition of hyper-phosphorylated MAPK and downstream intermediate S6 protein. In conclusion, depleted PTEN expression associated with mono-allelic PTEN loss occurs frequently in imatinib-resistant GIST and might serve as a biomarker for stratifying patients for optimal treatment. In vitro, the PTEN insufficiency leads to hyperactivation of AKT and MAPK pathways in tumor cells. Novel therapies targeting multiple components of the integrated KIT receptor signaling pathways in imatinibresistant GIST warrant further studies.

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Section: Discussionmentioning

confidence: 99%

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

et al. 2014

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“…Combination drugs that interfere with disease networks (so-called network medicine 66 ) have been shown to lead to a better response than single-hit therapies by causing secondary perturbations to signaling networks 47,48,67 . Recent work by the Yaffe laboratory represents a clear leap forward within the field of network medicine 68,69 .…”

Section: P E R S P E C T I V Ementioning

confidence: 99%

Navigating cancer network attractors for tumor-specific therapy

et al. 2012

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“…Feedback regulation of receptor tyrosine kinases (RTK) upon drug treatment has been amply described and is frequently implicated in resistance mechanisms to pathway-targeted therapies (20)(21)(22). We noticed in the response of HCC1806 cells to GDC-0941 that total levels of IGF1R protein steadily increase upon prolonged exposure to the drug.…”

Section: Levels Of the Ligand Igf2 Modulate The Sensitivity To Pi3k Imentioning

confidence: 82%

“…IGF1R has been suggested to play a role in ovarian cancer due to its upregulation after combined PI3K and mTOR inhibition (43) as well as in a range of ovarian cancer cell lines after AKT inhibition (20), but was not pursued with functional inhibitor experiments in these studies. These and other (44)(45)(46)(47) examples demonstrate that IGF1R inhibition may prove a valuable addition to inhibitors targeting the MAPK and PI3K pathways.…”

Section: Discussionmentioning

confidence: 99%

Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R

Lint

Poell

Soueidan

et al. 2016

Molecular Cancer Therapeutics

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Targeted therapies have proven invaluable in the treatment of breast cancer, as exemplified by tamoxifen treatment for hormone receptor-positive tumors and trastuzumab treatment for HER2-positive tumors. In contrast, a subset of breast cancer negative for these markers, triple-negative breast cancer (TNBC), has met limited success with pathway-targeted therapies. A large fraction of TNBCs depend on the PI3K pathway for proliferation and survival, but inhibition of PI3K alone generally has limited clinical benefit. We performed an RNAibased genetic screen in a human TNBC cell line to identify kinases whose knockdown synergizes with the PI3K inhibitor GDC-0941 (pictilisib). We discovered that knockdown of insulin-like growth factor-1 receptor (IGF1R) expression potently increased sensitivity of these cells to GDC-0941. Pharmacologic inhibition of IGF1R using OSI-906 (linsitinib) showed a strong synergy with PI3K inhibition. Furthermore, we found that the combination of GDC-0941 and OSI-906 is synergistic in 8 lines from a panel of 18 TNBC cell lines. In these cell lines, inhibition of IGF1R further decreases the activity of downstream PI3K pathway components when PI3K is inhibited. Expression analysis of the panel of TNBC cell lines indicates that the expression levels of IGF2BP3 can be used as a potential predictor for sensitivity to the PI3K/IGF1R inhibitor combination. Our data show that combination therapy consisting of PI3K and IGF1R inhibitors could be beneficial in a subset of TNBCs. Mol Cancer Ther; 15(7); 1545-56. Ó2016 AACR.

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AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity

Cited by 863 publications

References 36 publications

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

Navigating cancer network attractors for tumor-specific therapy

Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R

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