Epidemiologic evidence indicates that regular use of nonsteroidal anti-inflammatory drugs (
NSAIDs) provides a protective effect against the development of colorectal, breast, and head and
neck cancers. Genomic characterization of these
cancers has lent considerable insight into the subpopulations of
cancer patients who are most likely to benefit from
NSAID therapy. The PIK3CA gene encodes the catalytic subunit of
phosphatidylinositol 3-kinase (PI3K) and is among the most frequently mutated genes in solid
tumor malignancies.
Cancer-associated mutations in PIK3CA promote signaling via the PI3K pathway and stimulate
tumor cell growth. In addition, activation of the PI3K pathway leads to induction of
cyclooxygenase-2 (COX-2)
enzyme and production of immunosuppressive
prostaglandin E2 (
PGE2). Notably, in both
colorectal cancer and
head and neck cancer the subpopulation of patients that benefit from
NSAID use is restricted to those whose
tumors exhibit PIK3CA genomic alterations. Preclinical studies, particularly in models of
head and neck cancer, support the hypothesis that the chemopreventive impact of
NSAIDs may be due, in part, to inhibition of COX-2 and reduction of
PGE2 levels in the tumor microenvironment.