byl719 and Colorectal-Neoplasms

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Thiazoles

This was a cohort study on genetic alterations in patients with BRAF. In total, 37 patients were included in this cohort. Genetic alterations in EGFR and in PIK3CA are associated with non-response. A greater fraction of non-responders (75%) versus responders (46%) had at least one genetic alteration in other genes than TP53, APC or BRAF. Secondary resistance mutations (n = 16 patients) were observed most frequently in the PI3K pathway (n = 6) and in receptor tyrosine kinases (n = 4), leading to increased upstream signalling.. Genetic alterations in the PI3K and upstream receptor tyrosine kinases were mostly associated with intrinsic and acquired resistance. By understanding these alterations, simultaneous or alternating treatments with targeted inhibitors might improve response duration.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biomarkers, Tumor; Carbamates; Cetuximab; Cohort Studies; Colorectal Neoplasms; DNA Mutational Analysis; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Retrospective Studies; Sulfonamides; Thiazoles

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.

Topics: Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Survival; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; HCT116 Cells; Humans; Mutation; Proto-Oncogene Proteins p21(ras); RNA Interference; Signal Transduction; Thiazoles

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colorectal Neoplasms; Humans; Sulfonamides; Thiazoles