Circadian rhythm as a key player in cancer progression as well as a therapeutic target in HER2-positive advanced gastric cancer treatment

Gastric cancer is one of the most common cancer types with less than one year prognosis in metastatic disease, which poses a huge disease burden. One of the key players in poor prognosis is human epidermal growth factor receptor 2 (HER2), which also contributes to the pathogenesis of HER2-positive advanced gastric cancer. Trastuzumab is used as first-line chemotherapy that targets the expression of HER2, however, trastuzumab resistance is an inevitable major problem. To overcome this problem, readjustment of the circadian system may play a crucial role, as dysregulation in the expression of circadian clock genes has been observed in tumors. Therefore, pharmacological modulation of clock components can be considered for better efficacy of trastuzumab. In this review, we discuss the association of circadian clock with cancer progression, development, and treatment. Metformin-based chronotherapy can disrupt BMAL1-CLOCK-PER1-HK2 axis, thereby affecting glycolysis oscillation to overcome trastuzumab resistance in HER2-positive advanced gastric cancer.

Automated summary

Gastric cancer is a common cancer type with poor prognosis, especially in metastatic disease. The overexpression of HER2 is a major contributor to poor prognosis in HER2-positive advanced gastric cancer, and resistance to trastuzumab is a significant problem. Modulation of circadian clock genes may offer a solution to overcome trastuzumab resistance. This review discusses the association between circadian clock and cancer progression, development, and treatment, and proposes metformin-based chronotherapy as a potential approach to disrupt glycolysis oscillation and overcome trastuzumab resistance.