Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway

Sci Rep. 2015 Apr 20:5:9925. doi: 10.1038/srep09925.

Abstract

Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors. We here report that EGFR inhibition solely exhibited moderate inhibition in KRAS/NRAS/BRAF wildtype (triple-WT) MM cells, whilst had no effect in myeloma cells with any of the mutated genes. The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor. Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells. The inhibition could be restored by addition of NADPH. Dual EGFR/ERBB2 inhibitor Afatinib also exhibited similar effects. Further genetic silencing of EGFR, ERBB2 and mTOR indicated that major effect conferred by ERBB2 was via convergence to EGFR pathway in MM. Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Aminonicotinamide / pharmacology
  • Afatinib
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gefitinib
  • Glucose / metabolism
  • Humans
  • Metabolome / drug effects
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Oxygen / metabolism
  • Pentose Phosphate Pathway / drug effects*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / metabolism
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • RNA, Small Interfering / metabolism
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • ras Proteins / metabolism

Substances

  • Protein Kinase Inhibitors
  • Quinazolines
  • RNA, Small Interfering
  • 6-Aminonicotinamide
  • Afatinib
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • TOR Serine-Threonine Kinases
  • ras Proteins
  • Glucose
  • Gefitinib
  • Oxygen