Specific inhibition of p110α subunit of PI3K: putative therapeutic strategy for KRAS mutant colorectal cancers.
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.
Instituto de Investigação e Inovação em Saúde/Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
Maria Sofia
MS
Fernandes
Instituto de Investigação e Inovação em Saúde/Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.|Faculty of Medicine, University of Porto, Porto, Portugal.
Soraia
S
Melo
Instituto de Investigação e Inovação em Saúde/Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
Sérgia
S
Velho
Instituto de Investigação e Inovação em Saúde/Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
Patrícia
P
Carneiro
Instituto de Investigação e Inovação em Saúde/Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.|Faculty of Medicine, University of Porto, Porto, Portugal.|Department of Pathology, Centro Hospitalar São João, Porto, Portugal.
Fátima
F
Carneiro
Instituto de Investigação e Inovação em Saúde/Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.|Faculty of Medicine, University of Porto, Porto, Portugal.
Raquel
R
Seruca
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology
C117307:KRAS protein, human; D013844:Thiazoles; C585539:Alpelisib; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D016283:Proto-Oncogene Proteins p21(ras)
BYL719; KRAS; PI3K p110α; colorectal cancer; targeted therapies