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: 28.05). 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 · 2.28 Impact Factor
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    • "Given the prevalence of PIK3CA codon H1047 mutations in cancer, a critical consideration is whether patients with these mutations are at increased risk of malignancy. Transgenic expression of the Pik3ca p.His1047Arg mutation in lung [Engelman et al., 2008], or breast epithelium [Adams et al., 2011; Meyer et al., 2011] in mice has been shown to produce malignant tumors. However, in these studies mutant Pik3ca was overexpressed, potentially exaggerating its oncogenicity. "
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    ABSTRACT: Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2014; 164(7). DOI:10.1002/ajmg.a.36552 · 2.05 Impact Factor
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    • "AKT/mTOR and MAPK pathways is likely to result in resistance to the individual targeting of either pathway. Co-inhibition of both pathways has shown utility in reducing tumor growth in a variety of xenograft cancer models (Engelman et al. 2008; Hoeflich et al. 2009; Holt et al. 2012; Renshaw et al. 2013). Several trials that target the AKT/mTOR and MAPK pathways simultaneously are ongoing, utilizing the combination of AKT inhibitor plus MEK inhibitor or the combination of mTOR inhibitor and MEK inhibitor. "
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    ABSTRACT: Activation of numerous pathways has been documented in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) has emerged as a common therapeutic target. The mitogen-activated protein kinase (MAPK) and AKT signaling pathways are downstream of EGFR and deregulated via genetic and epigenetic mechanisms in many human cancers. We evaluated selected markers in the EGFR pathway with reference to outcome. Tissues from 220 cases of NSCLC patients presented in a tissue microarray were assayed with immunohistochemistry for phosphorylated AKT, phosphorylated MAPK, phosphorylated mTOR, and EGFR and then quantified by automated image analysis. Individually, the biomarkers did not predict. Combined as ratios, p-mTOR/p-AKT, and p-MAPK/EGFR function as prognostic markers of survival (p=0.008 and p=0.029, respectively), however, no significance was found after adjustment (p=0.221, p=0.103). The sum of these ratios demonstrates a stronger correlation with survival (p<0.001) and remained statistically significant after adjustment (p=0.026). The algebraic combination of biomarkers offer the capacity to understand factors that predict outcome better than current approaches of evaluating biomarkers individually or in pairs. Our results show the sum of p-mTOR/p-AKT and p-MAPK/EGFR is a potential predictive marker of survival in NSCLC patients.
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