Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition

Leroy, Cédric; Ramos, Pedro Marques; Cornille, Karen; Bonenfant, Débora; Fritsch, Christine; Voshol, Hans; Bentires‐Alj, Mohamed

doi:10.1186/s13058-016-0697-1

Cited by 74 publications

(47 citation statements)

References 30 publications

(37 reference statements)

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“…There are evidences to date, suggesting that resistance of CRC to dual PI3K/mTOR -targeted therapy can occur via several routes; dysregulation of the KRAS-RAF-MEK pathway, 10,36 activation of ERBB2 and ERBB3 through FOXO3a, 37 c-Myc induction by the Notch pathway, 38 and/or activation of the IGF1R/AKT pathway. 39 The present study is the first to suggest a WNT/βcatenin signaling-related mechanism of gedatolisib resistance in PIK3CA-mutant CRC.…”

Section: Discussionmentioning

confidence: 61%

Activation of WNT/β‐catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations

Park

Kim

Cho

et al. 2018

Intl Journal of Cancer

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PIK3CA is a frequently mutated gene in cancer, including about ~15 to 20% of colorectal cancers (CRC). PIK3CA mutations lead to activation of the PI3K/AKT/mTOR signaling pathway, which plays pivotal roles in tumorigenesis. Here, we investigated the mechanism of resistance of PIK3CA-mutant CRC cell lines to gedatolisib, a dual PI3K/mTOR inhibitor. Out of a panel of 29 CRC cell lines, we identified 7 harboring one or more PIK3CA mutations; of these, 5 and 2 were found to be sensitive and resistant to gedatolisib, respectively. Both of the gedatolisib-resistant cell lines expressed high levels of active glycogen synthase kinase 3-beta (GSK3β) and harbored the same frameshift mutation (c.465_466insC; H155fs*) in TCF7, which encodes a positive transcriptional regulator of the WNT/β-catenin signaling pathway. Inhibition of GSK3β activity in gedatolisib-resistant cells by siRNA-mediated knockdown or treatment with a GSK3β-specific inhibitor effectively reduced the activity of molecules downstream of mTOR and also decreased signaling through the WNT/β-catenin pathway. Notably, GSK3β inhibition rendered the resistant cell lines sensitive to gedatolisib cytotoxicity, both in vitro and in a mouse xenograft model. Taken together, these data demonstrate that aberrant regulation of WNT/β-catenin signaling and active GSK3β induced by the TCF7 frameshift mutation cause resistance to the dual PI3K/mTOR inhibitor gedatolisib. Cotreatment with GSK3β inhibitors may be a strategy to overcome the resistance of PIK3CA- and TCF7-mutant CRC to PI3K/mTOR-targeted therapies.

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Section: Discussionmentioning

confidence: 61%

Activation of WNT/β‐catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations

Park

Kim

Cho

et al. 2018

Intl Journal of Cancer

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“…mTOR is associated with various biological processes including cell proliferation, differentiation, migration and invasion, angiogenesis, survival as well as tumorigenesis . Recent studies demonstrated that mTOR also plays an important role in chemotherapeutic resistance . Moreover, PI3K/Akt/mTOR signaling pathway is associated with prostate cancer radioresistance .…”

Section: Discussionmentioning

confidence: 99%

Up‐regulation of miR‐497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl‐2

Zhu

Zeng

et al. 2017

Cancer Medicine

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The occurrence of an inherent or acquired resistance to temozolomide (TMZ) is a major burden for patients suffering from glioma. Recently, studies have demonstrated that microRNAs play an important role in the regulation of tumor properties in cancers. However, whether miR‐497 contributes to glioma resistance to chemotherapy is not fully understood. In this study, we showed that the expression of miR‐497 was markedly up‐regulated in TMZ‐resistant glioma cells; high miR‐497 expression level was associated with TMZ‐resistant phenotype of glioma cells. The down‐regulation of miR‐497 in glioma cells enhanced the apoptosis‐induction and growth inhibition effects of TMZ both in vitro and in vivo, whereas promotion of miR‐497 increased the chemosensitization of glioma cells to TMZ. The increased level of miR‐497 in TMZ‐resistant glioma cells was concurrent with the up‐regulation of insulin‐like growth factor 1 receptor (IGF1R)/insulin receptor substrate 1 (IRS1) pathway‐related proteins, that is, IGF1R, IRS1, mammalian target of rapamycin (mTOR), and Bcl‐2. In addition, the knockdown of mTOR and Bcl‐2 reduced the tolerance of glioma cells to TMZ. Our results demonstrated that overexpression of miR‐497 is significantly correlated with TMZ resistance in glioma cells by regulating the IGF1R/IRS1 pathway. Therefore, miR‐497 may be used as a new target for treatment of chemotherapy‐resistant glioma.

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“…PI3K signaling is upregulated in an estimated 70% of breast cancers (Leroy et al 2016), whether as a consequence of increased IGF1R (or EGFR) pathway activation, or secondary to oncogenic mutations in PIK3CA, reported to occur in about 25% of all breast cancers (Zardavas et al 2014). IGF1R pathway activation is known to confer resistance to PI3K inhibition (Leroy et al 2016), suggesting the possible utility of combined IGF1R/PI3K inhibition.…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

“…IGF1R pathway activation is known to confer resistance to PI3K inhibition (Leroy et al 2016), suggesting the possible utility of combined IGF1R/PI3K inhibition. A phase 1/2 clinical trial that commenced in 2012 has tested the effectiveness of a dual therapy comprising AMG479 and the PI3K-inhibitor, BYL719, in PIK3CA-mutated or -amplified solid cancers (Tables 1 and 2: Ref #7, NCT01708161).…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

Ochnik

Baxter

2016

Endocrine-Related Cancer

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Insulin-like growth factor receptor (IGF1R) signaling as a therapeutic target has been widely studied and clinically tested. Despite the vast amount of literature supporting the biological role of IGF1R in breast cancer, effective clinical translation in targeting its activity as a cancer therapy has not been successful. The intrinsic complexity of cancer cell signaling mediated by many tyrosine kinase growth factor receptors that work together to modulate each other and intracellular downstream mediators in the cell highlights that studying IGF1R expression and activity as a prognostic factor and therapeutic target in isolation is certainly associated with problems. This review discusses the current literature and clinical trials associated with IGF-1 signaling and attempts to look at new ways of designing novel IGF1R-directed breast cancer therapy approaches to target its activity and/or intracellular downstream signaling pathways in IGF1R-expressing breast cancers. 23:11 Review A M Ochnik and R C BaxterDual IGF-directed breast cancer therapies

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Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition

Cited by 74 publications

References 30 publications

Activation of WNT/β‐catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations

Activation of WNT/β‐catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations

Up‐regulation of miR‐497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl‐2

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

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