Specific inhibition of p110 alpha subunit of PI3K: putative therapeutic strategy for KRAS mutant colorectal cancers

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Fernandes, MS (Author) Other; Melo, S (Author) Other; Velho, S (Author) Other; Carneiro, P (Author) Other; Carneiro F (Author) FMUP; Seruca, R (Author) Other

Journal

Title: Oncotarget

Vol. 7

Pages: 68546-68558

ISSN: 1949-2553

Publisher: Impact Journals

Indexing

ISI Web of Knowledge - 8 Citations

Scopus - 9 Citations

Other information

Authenticus ID: P-00M-7QK

DOI: 10.18632/oncotarget.11843

Abstract (EN): 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 p110 alpha a key role in CRC cells harboring KRAS/PIK3CA mutations or KRAS mutations alone. Specific silencing of PI3K p110a by small interfering RNA (siRNA) reduced viability and induced apoptosis or cell cycle arrest. In agreement with these cellular effects, PI3K p110 alpha 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 p110a 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 p110 alpha could provide an alternative therapeutic approach for CRC patients, particularly those harboring KRAS mutations.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13