Aspirin sensitivity of PIK3CA-mutated Colorectal Cancer: potential mechanisms revisited
Daniella C N Hall1, Ralf A Benndorf2
1Department of Clinical Pharmacy and Pharmacotherapy, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120, Halle (Saale), Germany.
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.
Insights
Acetylsalicylic acid (aspirin) may benefit cancer patients with PIK3CA mutations, potentially via COX-independent pathways. This review explores mechanisms behind aspirin
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- PIK3CA mutations are common in cancer, linked to treatment resistance and poor survival.
- Acetylsalicylic acid (aspirin) shows potential therapeutic benefits for PIK3CA-mutated cancers, especially colorectal cancer.
- PIK3CA encodes the p110α subunit of Class IA Phosphatidylinositol 3-kinases (PI3K), crucial in cell regulation.
- PI3K signaling is implicated in cancer development, and its link to cyclooxygenase-2 (COX-2) and aspirin is known but not fully understood.
- Aspirin's anti-cancer effects may involve COX-independent mechanisms, warranting further investigation.
Purpose of the Study:
- To review current literature on the therapeutic potential of aspirin in PIK3CA-mutated cancers.
- To analyze potential COX-independent mechanisms and molecular targets mediating aspirin's effect.
- To elucidate the relationship between PIK3CA mutations, PI3K signaling, and aspirin sensitivity.
Main Methods:
- Literature review of existing studies on PIK3CA mutations, aspirin therapy, and cancer.
- Analysis of molecular pathways involving PI3K, COX-2, and prostaglandins.
- Exploration of potential prostaglandin-independent targets of aspirin in cancer.
Main Results:
- Evidence suggests PIK3CA mutations confer sensitivity to aspirin, particularly in colorectal cancer.
- While PI3K is linked to COX-2, aspirin's efficacy may not solely depend on COX inhibition.
- The precise mechanisms of aspirin's COX-independent action in PIK3CA-mutated cancers remain largely unclear.
Conclusions:
- PIK3CA-mutated cancers represent a potential target population for aspirin therapy.
- Further research is needed to fully understand aspirin's prostaglandin-independent mechanisms of action.
- Identifying these mechanisms could lead to novel therapeutic strategies for PIK3CA-driven malignancies.
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