Abstract:
Background: Regular aspirin use has been associated with improved survival in colorectal cancer (CRC) patients with PIK3CA-mutant tumours (Liao et al., 2012). Since CRC cells possess common mutations in PIK3CA, KRAS, BRAF, and APC, which can sensitise cells to targeted therapies, this study aimed to determine if aspirin could interact with p110α-selective (A66) or mTOR/pan phosphoinositide 3-kinase (PI3K) inhibitors (BEZ235), a MEK inhibitor (selumetinib), or a WNT signalling inhibitor (pyrvinium) to delay CRC growth. Method: A panel of nine CRC cell lines with differing mutations in PIK3CA, KRAS, BRAF and APC were treated with aspirin, A66, BEZ235, selumetinib, and pyrvinium alone and in combination to investigate the effects of these compounds on cell viability and AKT phosphorylation. The in vivo antitumour activity of aspirin alone and in combination with A66 or BEZ235 was evaluated in an HCT116 tumour xenograft model. Results: No significant differences in sensitivity to aspirin, A66, and BEZ235 were found between PIK3CA mutant and wildtype cells, whereas a significant difference in sensitivity to 10μM selumetinib was found between BRAF mutant and wildtype cells. Combining aspirin with the targeted agents significantly reduced cell viability to a greater extent than either agent alone, except for BEZ235, in at least 2 cell lines, but was no more effective in mutant than wildtype cells. The addition of aspirin to A66 or BEZ235 did not alter pAKT expression, except for a possible reduction in phosphorylation at S473 when combined with A66 in HCT116 cells. Combination treatment of aspirin with A66 or BEZ235 had no effect on HCT116 tumour growth. Discussion: The results showed that some concentrations of aspirin in combination with targeted agents could reduce CRC cell viability to a greater extent than the targeted agents alone. However, the increased response was minimal, required high doses of aspirin that are not clinically relevant, and was no more prevalent in mutant or wildtype CRC cells. Also aspirin combined with PI3K inhibitors offered no great benefit at inhibiting pAKT expression and HCT116 tumour growth. Overall, these results do not support the use of aspirin in combination with targeted therapies in delaying the growth of CRC.