Targeting the PI3K/Akt/mTOR Pathway – Beyond Rapalogs

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Abstract

It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.

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Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.

Arkaitz Carracedo, Li Ma, Julie Teruya-Feldstein … (2008)

Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.

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An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.

Katherine Stemke-Hale, Ana Maria Gonzalez-Angulo, Ana Lluch … (2008)

Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor-positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor-positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

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A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.

John D Carpten, Andrew L Faber, Candice Horn … (2007)

Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: November 2010

Publication date (Electronic): 22 October 2010

Volume: 1

Issue: 7

Pages: 530-543

Affiliations

¹ Centre for Cancer Research, Monash Institute of Medical Research, Southern Health, Melbourne, Victoria, Australia

² Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain

Author notes

Correspondence to: Josep Tabernero, jtabernero@ 123456vhio.net

Article

DOI: 10.18632/oncotarget.188

PMC ID: 3248125

PubMed ID: 21317449

SO-VID: d547f9d9-2703-45e9-af47-22e280f37392

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Targeting the PI3K/Akt/mTOR Pathway – Beyond Rapalogs

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Karger: Oncology

Most cited references 59

Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.

An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.

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