Article

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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    • "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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    • "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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