AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta-analysis using TRIBE, MAVERICC and FIRE3

Ryuma Tokunaga, Shu Cao, Madiha Naseem, Francesca Battaglin, Jae Ho Lo, Hiroyuki Arai, Fotios Loupakis, Sebastian Stintzing, Alberto Puccini, Martin D Berger, Shivani Soni, Wu Zhang, Christoph Mancao, Bodour Salhia, Shannon M Mumenthaler, Daniel J Weisenberger, Gangning Liang, Chiara Cremolini, Volker Heinemann, Alfredo FalconeJoshua Millstein, Heinz-Josef Lenz

Research output: Contribution to journalArticle

Abstract

AMP-activated protein kinase (AMPK) is a key sensor of energy homeostasis and regulates cell metabolism, proliferation and chemotherapy/radiotherapy sensitivities. This study aimed to explore the relationship between the AMPK pathway-related single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with metastatic colorectal cancer (mCRC). We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC and FIRE-3: where patients were treated with FOLFIRI, mFOLFOX6 or FOLFOXIRI combined with bevacizumab or cetuximab as the first-line chemotherapy). The association between AMPK pathway-related SNPs and clinical outcomes was analyzed across the six treatment cohorts, using a meta-analysis approach. Our meta-analysis showed that AMPK pathway had significant associations with progression-free survival (PFS; p < 0.001) and overall survival (OS; p < 0.001), but not with tumor response (TR; p = 0.220): PRKAA1 rs13361707 was significantly associated with favorable PFS (log HR = -0.219, SE = 0.073, p = 0.003), as well as PRKAA1 rs10074991 (log HR = -0.215, SE = 0.073, p = 0.003), and there were suggestive associations of PRKAG1 rs1138908 with unfavorable OS (log HR = 0.170, SE = 0.083, p = 0.041), and of UBE2O rs3803739 with unfavorable PFS (log HR = 0.137, SE = 0.068, p = 0.042) and OS (log HR = 0.210, SE = 0.077, p = 0.006), although these results were not significant after false discovery rate adjustment. AMPK pathway-related SNPs may be predictors for chemotherapy in mCRC. Upon validation, our findings would provide novel insight for selecting treatment strategies.

Original languageEnglish
Pages (from-to)2082-2090
Number of pages9
JournalInternational Journal of Cancer
Volume145
Issue number8
DOIs
Publication statusPublished - Oct 15 2019

Keywords

  • AMP-Activated Protein Kinases/genetics
  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Bevacizumab/administration & dosage
  • Biomarkers, Tumor/genetics
  • Camptothecin/administration & dosage
  • Cetuximab/administration & dosage
  • Colorectal Neoplasms/drug therapy
  • Fluorouracil
  • Humans
  • Leucovorin/administration & dosage
  • Neoplasm Metastasis
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Progression-Free Survival
  • Randomized Controlled Trials as Topic
  • Signal Transduction/genetics

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    Tokunaga, R., Cao, S., Naseem, M., Battaglin, F., Lo, J. H., Arai, H., Loupakis, F., Stintzing, S., Puccini, A., Berger, M. D., Soni, S., Zhang, W., Mancao, C., Salhia, B., Mumenthaler, S. M., Weisenberger, D. J., Liang, G., Cremolini, C., Heinemann, V., ... Lenz, H-J. (2019). AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta-analysis using TRIBE, MAVERICC and FIRE3. International Journal of Cancer, 145(8), 2082-2090. https://doi.org/10.1002/ijc.32261