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

Abstract

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.

Keywords: cancer treatment; circadian rhythm; epidermal growth factor receptor 2; gastric cancer; trastuzumab.

Figure 1

This figure represents the molecular mechanism of the circadian clock in mammals.

Figure 2

Left: Chronotherapy improves host tolerance and safety against anticancer medicine. To reduce toxicity, dihydropyrimidine dehydrogenase (DPD), 5-FU (an elimination enzyme), and thymidine synthase (TS) play crucial role. Glutathione (GSH), a chronotolerance biomarker is important when oxaliplatin and cisplatin or other platinum based anti-cancer drugs are used. Doxorubicin causes fewer side effects and more therapeutic effects when used in the morning. Circadian rhythms can be targeted by cycle-specific anticancer drugs, while circadian clock function regulates cell cycle rhythms in tumors, which can mediate time-dependent cytotoxicity of antitumor drugs. Importantly, BMAL1 tumor circadian rhythms, cell cycle rhythm and anticancer drug activity rhythm, therefore, targeting BMAL1 in anticancer drug therapy can improve therapeutic response. Right: This figure shows that circadian oscillation of HK2 dependent glycolysis exists in HER2- positive advanced gastric cancer. Chronotherapy using metformin can disrupt rhythm of PER1-HK2, thereby reversing trastuzumab resistance. This modified figure was adopted from Wang et al. (6).

Figure 3

Left: (A) Circadian rhythm modulates physiological behavior by regulating hormonal release. (B) Circadian system interacts with pathways associated with metabolism and cellular homeostasis. Disrupted circadian clock induces cancer progression and development; normal rhythms can be restored by chronotherapeutic interventions to improve the efficacy anticancer therapeutics/treatments. Right: PER1 can cause reversal of trastuzumab resistance. (A) Injecting transfected NCI-N87TR cells into nude mice and measurement of glycolysis level shown PET-CT images, where white circles detect location of the tumor. (B) Standard uptake value (mean values), (C) PER1 and HK2 expression indicated by IHC images, (D) Levels of PER1 and HK2 detected by quantitative analysis, (E) Tumor growth in response to the treatment with trastuzumab and PER1 knockdown, (F) Ki67 and cleavage of caspase-3 detected by IHC images. This figure was adopted from Wang et al. (6).