Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

[1] Massachusetts General Hospital Cancer Center, 149 Thirteenth Street, Charlestown, Massachusetts 02129, USA. [2] Beth Israel Deaconness Medical Center Cancer Center, Beth Israel Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. [3] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA. [4] These authors contributed equally to this work.
Nature Medicine (Impact Factor: 27.36). 11/2008; 14(12):1351-1356. DOI: 10.1038/nm.1890

ABSTRACT Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110- catalytic subunit (encoded by PIK3CA)1. They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110- mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered a mouse model of lung adenocarcinomas initiated and maintained by expression of p110- H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan–PI3K and mammalian target of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression as shown by positron emission tomography–computed tomography, magnetic resonance imaging and microscopic examination. In contrast, mouse lung cancers driven by mutant Kras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a mitogen-activated protein kinase kinase (MEK) inhibitor, ARRY-142886, there was marked synergy in shrinking these Kras-mutant cancers. These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRAS mutated lung cancers.

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Available from: Liang Chen, Sep 30, 2014
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    • "Animal models are a vital resource in the search for improved methods of diagnosis and treatment. For example, different human KRAS-driven cancers can vary widely in their response to targeted therapies (Pylayeva-Gupta et al. 2011; Engelman et al. 2008). Comparison of mouse Kras models of pancreatic and lung cancer has revealed critical differences in oncogenic Kras signalling between these organs that explain this diversity, and identified possible new targets for therapeutic intervention (Eser et al. 2013). "
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    ABSTRACT: Oncogenic mutations of KRAS play a major role in human carcinogenesis. Here we describe viable gene-targeted pigs carrying a latent KRAS G12D mutant allele that can be activated by Cre recombination. These have been produced as part of a program to model human cancers in pigs by replicating genetic lesions known to initiate and drive human disease. Cre-activated KRAS G12D animals add to a growing set of gene-targeted pigs that includes a Cre-activated oncogenic mutant TP53, a Cre-responsive dual fluorescent reporter and two truncating mutations of APC (adenomatous polyposis coli). These alleles can be combined and activated in various tissues to produce new models for cancer research.
    Transgenic Research 02/2015; 24(3). DOI:10.1007/s11248-015-9866-8 · 2.32 Impact Factor
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    • "In our study, because TET1 re-expression blocks transformation and because TET1 knockdown can allow KRAS knockdown cells to retain a malignant phenotype, we identified TET1 repression as a critical component of the RAS program. Several inhibitors of the EGF receptor-RAS-RAF-MEK-ERK axis are under development (Downward, 2003; Engelman et al., 2008; Karapetis et al., 2008; Pao and Chmielecki, 2010). Because these drugs may depend on reactivating TET1 expression for efficacy, TET1 rerepression or increased 5hmC may serve as clinically important biomarkers of functional reversion of RAS transformation. "
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    ABSTRACT: Hypermethylation-mediated tumor suppressor gene (TSG) silencing is a central epigenetic alteration in RAS-dependent tumorigenesis. Ten-eleven translocation (TET) enzymes can depress DNA methylation by hydroxylation of 5-methylcytosine (5mC) bases to 5-hydroxymethylcytosine (5hmC). Here, we report that suppression of TET1 is required for KRAS-induced DNA hypermethylation and cellular transformation. In distinct nonmalignant cell lines, oncogenic KRAS promotes transformation by inhibiting TET1 expression via the ERK-signaling pathway. This reduces chromatin occupancy of TET1 at TSG promoters, lowers levels of 5hmC, and increases levels of 5mC and 5mC-dependent transcriptional silencing. Restoration of TET1 expression by ERK pathway inhibition or ectopic TET1 reintroduction in KRAS-transformed cells reactivates TSGs and inhibits colony formation. KRAS knockdown increases TET1 expression and diminishes colony-forming ability, whereas KRAS/TET1 double knockdown bypasses the KRAS dependence of KRAS-addicted cancer cells. Thus, suppression of TET1-dependent DNA demethylation is critical for KRAS-mediated transformation. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 11/2014; 9(5). DOI:10.1016/j.celrep.2014.10.063 · 8.36 Impact Factor
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    • "Dual inhibition of the MEK and PI3K/mTOR pathways has shown preclinical promise as a therapeutic strategy in a variety of tumors [24]–[26], [28], [40]–[42] and has entered into phase 1 trials in humans [29]. Inhibition of the MEK/ERK and PI3K/mTOR pathways is a rational strategy based on the extensive crosstalk between the two pathways and the well documented compensatory signaling that occurs in the face of MEK or mTOR inhibition [37]. "
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    ABSTRACT: Rapamycin derivatives allosterically targeting mTOR are currently FDA approved to treat advanced renal cell carcinoma (RCC), and catalytic inhibitors of mTOR/PI3K are now in clinical trials for treating various solid tumors. We sought to investigate the relative efficacy of allosteric versus catalytic mTOR inhibition, evaluate the crosstalk between the mTOR and MEK/ERK pathways, as well as the therapeutic potential of dual mTOR and MEK inhibition in RCC. Pharmacologic (rapamycin and BEZ235) and genetic manipulation of the mTOR pathway were evaluated by in vitro assays as monotherapy as well as in combination with MEK inhibition (GSK1120212). Catalytic mTOR inhibition with BEZ235 decreased proliferation and increased apoptosis better than allosteric mTOR inhibition with rapamycin. While mTOR inhibition upregulated MEK/ERK signaling, concurrent inhibition of both pathways had enhanced therapeutic efficacy. Finally, primary RCC tumors could be classified into subgroups [(I) MEK activated, (II) Dual MEK and mTOR activated, (III) Not activated, and (IV) mTOR activated] based on their relative activation of the PI3K/mTOR and MEK pathways. Patients with mTOR only activated tumors had the worst prognosis. In summary, dual targeting of the mTOR and MEK pathways in RCC can enhance therapeutic efficacy and primary RCC can be subclassified based on their relative levels of mTOR and MEK activation with potential therapeutic implications.
    PLoS ONE 09/2014; 9(9):e104413. DOI:10.1371/journal.pone.0104413 · 3.23 Impact Factor
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