Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus

Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, IRCC, University of Turin Medical School, Turin, Italy.
The Journal of clinical investigation (Impact Factor: 13.77). 08/2010; 120(8):2858-66. DOI: 10.1172/JCI37539
Source: PubMed

ABSTRACT Personalized cancer medicine is based on the concept that targeted therapies are effective on subsets of patients whose tumors carry specific molecular alterations. Several mammalian target of rapamycin (mTOR) inhibitors are in preclinical or clinical trials for cancers, but the molecular basis of sensitivity or resistance to these inhibitors among patients is largely unknown. Here we have identified oncogenic variants of phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) and KRAS as determinants of response to the mTOR inhibitor everolimus. Human cancer cells carrying alterations in the PI3K pathway were responsive to everolimus, both in vitro and in vivo, except when KRAS mutations occurred concomitantly or were exogenously introduced. In human cancer cells with mutations in both PIK3CA and KRAS, genetic ablation of mutant KRAS reinstated response to the drug. Consistent with these data, PIK3CA mutant cells, but not KRAS mutant cells, displayed everolimus-sensitive translation. Importantly, in a cohort of metastatic cancer patients, the presence of oncogenic KRAS mutations was associated with lack of benefit after everolimus therapy. Thus, our results demonstrate that alterations in the KRAS and PIK3CA genes may represent biomarkers to optimize treatment of patients with mTOR inhibitors.

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Available from: Federica Di Nicolantonio, Aug 18, 2015
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    • "Our group and others showed that, in colorectal and gynecological cancers, PIK3CA mutations often coexist with mutations in the MAPK pathway such as KRAS and BRAF mutations, which can abrogate response to PI3K/AKT/mTOR pathway inhibitors (De Roock et al., 2010; Di Nicolantonio et al., 2010; Engelman et al., 2008; Ihle et al., 2009; Janku et al., 2011a, 2012b). The current study confirms preclinical findings demonstrating that mutations in the MAPK pathway are associated with an attenuated response rate to PI3K/AKT/mTOR inhibitors (Di Nicolantonio et al., 2010; Engelman et al., 2008; Ihle et al., 2009). Furthermore, "
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    ABSTRACT: Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN) gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589), and PTEN loss and/or mutation was found in 13% (149/1,157). In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.
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    • "Among others, these biomarkers include inactivation of PTEN, activating mutations of PI3KCA, expression levels of pS6, pS6K, S6K, and pAkt. Interestingly, a study demonstrated that human cancer cell lines carrying PI3KCA mutations were responsive to everolimus, except when KRAS mutations occurred concomitantly [99]. Similar results were obtained in a study with colon cancer cell lines [100], and mTOR resistance was also shown in ovarian cancer cell lines, which overexpressed the apoptosis-inhibitory protein Bcl2 [101]. "
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    ABSTRACT: Mechanistic target of rapamycin (mTOR) regulates cell growth, metabolism and aging in response to nutrients, cellular energy stage and growth factors. mTOR is frequently up-regulated in cancer including hepatocellular carcinoma (HCC) and is associated with bad prognosis, poorly differentiated tumors, and earlier recurrence. Blocking mTOR with rapamycin and first generation mTOR inhibitors, called rapalogs, has shown promising reduction of HCC tumors growth in preclinical models. Currently, rapamycin/rapalogs are used in several clinical trials for the treatment of advanced HCC, and as adjuvant therapy in HCC patients after liver transplantation and TACE. A second generation of mTOR pathway inhibitors has been developed recently, and is being tested in various clinical trials of solid cancers and has been used in preclinical HCC models. The results of series of clinical trials using mTOR inhibitors in HCC treatment will emerge in the near future.
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    • "Intrinsic resistance. KRAS-mutated cancers exhibit intrinsic resistance against mTOR inhibition in vitro, in mouse models and in patients (Di Nicolantonio et al., 2010). Mutations in KRAS were also suggested to cause intrinsic resistance to a pan-class I PI3K inhibitor in vitro (Maira et al., 2012). "
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    ABSTRACT: The widespread hyperactivation of the PI3K/mTOR pathway in human cancer has made it a prime target for the treatment of this disease. However, a variety of resistance mechanisms involving (re)activation of the targeted pathway or of parallel survival signaling cascades have limited the clinical success of inhibitors targeting PI3K and/or mTOR. Recent studies delineated new crosstalks between PI3K, HER2, JAK2 and IL-8 signaling, which can explain the limited efficacy of PI3K blockade when inhibitors of this pathway are used as single agents. In this review, we summarize molecular mechanisms of resistance to inhibitors of the PI3K/mTOR pathway, provide an outline of new connections between crucial oncogenic signaling pathways, and discuss the potential of new combination therapy approaches to overcome resistance.
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