Aspirin sensitivity of PIK3CA-mutated Colorectal Cancer: potential mechanisms revisited

Abstract

PIK3CA mutations are amongst the most prevalent somatic mutations in cancer and are associated with resistance to first-line treatment along with low survival rates in a variety of malignancies. There is evidence that patients carrying PIK3CA mutations may benefit from treatment with acetylsalicylic acid, commonly known as aspirin, particularly in the setting of colorectal cancer. In this regard, it has been clarified that Class IA Phosphatidylinositol 3-kinases (PI3K), whose catalytic subunit p110α is encoded by the PIK3CA gene, are involved in signal transduction that regulates cell cycle, cell growth, and metabolism and, if disturbed, induces carcinogenic effects. Although PI3K is associated with pro-inflammatory cyclooxygenase-2 (COX-2) expression and signaling, and COX-2 is among the best-studied targets of aspirin, the mechanisms behind this clinically relevant phenomenon are still unclear. Indeed, there is further evidence that the protective, anti-carcinogenic effect of aspirin in this setting may be mediated in a COX-independent manner. However, until now the understanding of aspirin’s prostaglandin-independent mode of action is poor. This review will provide an overview of the current literature on this topic and aims to analyze possible mechanisms and targets behind the aspirin sensitivity of PIK3CA-mutated cancers.

Aspirin and cancer survival-related pathways: a review and analysis of molecular mechanisms

“…The rst group includes primary genes controlled directly by aspirin, i.e., PTGS2 and PTGES2. The second group consists of genes involved in cell signaling and cell proliferation like cMyc, EGFR, BCL2, WNT, KRAS, WNT6, BRAF, MUC1, PIK3CA, PARP1, PARP2, STAT3, MAPK, JAK/STAT, BAX 6,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] ; the third group, genes for cytokines or their receptors (e.g., IFNγ, IL1β, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12 (p70), IL13, IL17, CXCR1, CXCR2, PTGS2, PTGES2, NFKB1, and TNFα); 30,[33][34][35][36][37][38][39][40][41][42] and the fourth group, tumor suppressor genes including P53, BRCA1, 43 hMLH1, hMSH2, hMSH6, hPMS2 44,45 (Table 1).…”

Aspirin boosts the synergistic effect of EGFR/p53 inhibitors on lung cancer cells by regulating AKT/mTOR and p53 pathways

“…Furthermore, several signaling pathways are regulated in the antitumor process of aspirin. The PI3K/AKT/mTOR pathway is a classic signaling pathway that regulates cell survival, proliferation, metabolism, and growth, which is a promising target for antitumor agents including aspirin 21 . Several reports have shown that aspirin sensitized cancer cell to other agents by suppressing the AKT/mTOR pathways in colorectal cancer, breast cancer, or lung cancer 16,20,22,30 .…”

“…Aspirin is a commonly used anti‐inflammatory drug, while it has provided important information on the prevention and treatment of several types of cancer 11–13 . Aspirin alone or in combination with other agents has shown unique efficacy in the process of cancer treatment in preclinical experiments 14–22 . In the present study, we first investigated the effect and mechanism of triple therapy with aspirin, afatinib, and vinorelbine on three types of p53 wild‐type NSCLC cells.…”

Elucidating the mechanism of Hongjinshen decoction in the treatment of pulmonary fibrosis based on network pharmacology and molecular docking

“…The PIK3CA gene, which encodes the catalytic subunit p110α of class IA PI3K, can be mutated in a variety of cancers, such as head and neck squamous cell carcinoma, breast cancer, lung cancer, hepatocellular carcinoma, and ovarian cancer, among others. [ 19 ] Mutations in PIK3CA in cancer have been shown to be strongly associated with poor prognosis and resistance to standard treatments such as monoclonal antibody therapy and chemotherapy in cancer patients. [ 20 ] Not only cancer, PIK3CA is also associated with a variety of fibrotic diseases.…”