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

Int J Cancer. 2019 Oct 15;145(8):2082-2090. doi: 10.1002/ijc.32261. Epub 2019 Mar 26.

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.

Keywords: AMPK; SNP; chemotherapy; metastatic colorectal cancer; variant.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Fluorouracil
  • Humans
  • Leucovorin / administration & dosage
  • Neoplasm Metastasis
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Progression-Free Survival
  • Randomized Controlled Trials as Topic
  • Signal Transduction / genetics

Substances

  • Biomarkers, Tumor
  • Bevacizumab
  • PRKAA1 protein, human
  • AMP-Activated Protein Kinases
  • Cetuximab
  • Leucovorin
  • Fluorouracil
  • Camptothecin