Specific inhibition of p110α subunit of PI3K: putative therapeutic strategy for KRAS mutant colorectal cancers
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Maria Sofia Fernandes1,2, Soraia Melo1,2,3, Sérgia Velho1,2, Patrícia Carneiro1,2, Fátima Carneiro1,2,3,4, Raquel Seruca1,2,3
1Instituto de Investigação e Inovação em Saúde/Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
2Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
3Faculty of Medicine, University of Porto, Porto, Portugal
4Department of Pathology, Centro Hospitalar São João, Porto, Portugal
Raquel Seruca, email: [email protected]
Keywords: colorectal cancer, targeted therapies, PI3K p110α, KRAS, BYL719
Received: April 05, 2016 Accepted: August 24, 2016 Published: September 02, 2016
Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. It is often associated with activating mutations in KRAS leading to deregulation of major signaling pathways as the RAS-RAF-MAPK and PI3K-Akt. However, the therapeutic options for CRC patients harboring somatic KRAS mutations are still very limited. It is therefore urgent to unravel novel therapeutic approaches for those patients. In this study, we have awarded PI3K p110α a key role in CRC cells harboring KRAS/PIK3CA mutations or KRAS mutations alone. Specific silencing of PI3K p110α by small interfering RNA (siRNA) reduced viability and induced apoptosis or cell cycle arrest. In agreement with these cellular effects, PI3K p110α silencing led to alterations in the expression levels of proteins implicated in apoptosis and cell cycle, namely XIAP and pBad in KRAS/PIK3CA mutant cells and cyclin D1 in KRAS mutant cells. To further validate our data, a specific PI3K p110α inhibitor, BYL719, was evaluated. BYL719 mimicked the in vitro siRNA effects on cellular viability and on the alterations of apoptotic- and cell cycle-related proteins in CRC mutant cells. Overall, this study demonstrates that specific inhibition of PI3K p110α could provide an alternative therapeutic approach for CRC patients, particularly those harboring KRAS mutations.
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