azd-6244 and Chromosomal-Instability

Gastric cancer is the second leading cause of death from cancer worldwide, with an approximately 20% 5-year survival rate. To identify molecular subtypes associated with the clinical prognosis, in addition to genetic aberrations for potential targeted therapeutics, we conducted a comprehensive whole-genome analysis of 131 Chinese gastric cancer tissue specimens using whole-genome array comparative genomic hybridization. The analyses revealed gene focal amplifications, including CTSB, PRKCI, PAK1, STARD13, KRAS, and ABCC4, in addition to ERBB2, FGFR2, and MET. The growth of PAK1-amplified gastric cancer cells in vitro and in vivo was inhibited when the corresponding mRNA was knocked down. Furthermore, both KRAS amplification and KRAS mutation were identified in the gastric cancer specimens. KRAS amplification was associated with worse clinical outcomes, and the KRAS gene mutation predicted sensitivity to the MEK1/2 inhibitor AZD6244 in gastric cancer cell lines. In summary, amplified PAK1, as well as KRAS amplification/mutation, may represent unique opportunities for developing targeted therapeutics for the treatment of gastric cancer.

Topics: Benzimidazoles; Chromosomal Instability; Cohort Studies; Female; Gene Amplification; Gene Dosage; Gene Expression Profiling; Genome, Human; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Mutation; p21-Activated Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; RNA, Messenger; Stomach Neoplasms; Survival Rate