1. Academic Validation
  2. Disrupting Circadian Rhythm via the PER1-HK2 Axis Reverses Trastuzumab Resistance in Gastric Cancer

Disrupting Circadian Rhythm via the PER1-HK2 Axis Reverses Trastuzumab Resistance in Gastric Cancer

  • Cancer Res. 2022 Apr 15;82(8):1503-1517. doi: 10.1158/0008-5472.CAN-21-1820.
Jiao Wang  # 1 Qiong Huang  # 1 Xingbin Hu  # 1 Shuyi Zhang  # 2 Yu Jiang 1 Guangyu Yao 3 Kongzhen Hu 4 Xin Xu 1 Bishan Liang 1 Qijing Wu 1 Zhenfeng Ma 1 Yawen Wang 1 Chunlin Wang 1 Zhenzhen Wu 1 Xiaoxiang Rong 1 Wangjun Liao 1 Min Shi 1
Affiliations

Affiliations

  • 1 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
  • 2 Department of Oncology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, People's Republic of China.
  • 3 Department of General Surgery, Breast Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
  • 4 Department of Nuclear Medicine, GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
  • # Contributed equally.
Abstract

Trastuzumab is the only approved targeted drug for first-line treatment of HER2-positive advanced gastric Cancer, but the high rate of primary resistance and rapid emergence of secondary resistance limit its clinical benefits. We found that trastuzumab-resistant (TR) gastric Cancer cells exhibited high glycolytic activity, which was controlled by Hexokinase 2 (HK2)-dependent glycolysis with a circadian pattern [higher at zeitgeber time (ZT) 6, lower at ZT18]. Mechanistically, HK2 circadian oscillation was regulated by a transcriptional complex composed of PPARγ and the core clock gene PER1. In vivo and in vitro experiments demonstrated that silencing PER1 disrupted the circadian rhythm of PER1-HK2 and reversed trastuzumab resistance. Moreover, metformin, which inhibits glycolysis and PER1, combined with trastuzumab at ZT6, significantly improved trastuzumab efficacy in gastric Cancer. Collectively, these data introduce the circadian clock into trastuzumab therapy and propose a potentially effective chronotherapy strategy to reverse trastuzumab resistance in gastric Cancer.

Significance: In trastuzumab-resistant HER2-positive gastric Cancer, glycolysis fluctuates with a circadian oscillation regulated by the BMAL1-CLOCK-PER1-HK2 axis, which can be disrupted with a metformin-based chronotherapy to overcome trastuzumab resistance.

Figures
Products