UTILITY OF PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS IN GASTROINTESTINAL CANCER

Abstract

INHIBITION OF THE PHOSPHATIDYLINOSITOL-3-KINASE (PI3K) SIGNALLING PATHWAY IS A CANCER TREATMENT STRATEGY THAT HAS ENTERED INTO CLINICAL TRIALS FOR GC AND CRC PATIENTS. THE AIMS OF THIS STUDY WERE 1) TO CHARACTERISE INTER-ETHNIC FREQUENCIES AND CO-OCCURRENCE PATTERNS OF PROMINENT PI3K PATHWAY ABERRATIONS IN GC AND CRC, AND 2) TO IDENTIFY PREDICTIVE BIOMARKERS FOR PI3K INHIBITORS IN GC AND CRC CELLS. THE META-ANALYSIS INDICATED THAT EAST ASIAN AND CAUCASIAN GC PATIENTS DIFFER SIGNIFICANTLY IN THE FREQUENCIES OF PIK3CA EXON 9 AND EXON 20 MUTATIONS, PTEN DELETION AND PTEN LOSS, WHILE CRC PATIENTS DIFFERED FOR PTEN LOSS. HIGH STUDY HETEROGENEITY WAS OBSERVED FOR ALL ABERRATIONS EXCEPT PIK3CA MUTATIONS. ANALYSIS OF TUMOURS FROM EAST ASIAN PATIENTS REVEALED SIGNIFICANT DIFFERENCES BETWEEN GC AND CRC FOR THE FREQUENCIES OF PIK3CA AMPLIFICATION AND PTEN LOSS. ONCOCARTA ANALYSIS REVEALED THAT PIK3CA MUTATION WAS ASSOCIATED WITH INCREASED SENSITIVITY TO PI3K INHIBITORS, AND KRAS (G12V) MUTATION W