title: Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway.
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.
authors.affiliation: Department of Haematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Haematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Ruibin
authors.initials: R
authors.lastname: Huang
authors.affiliation: Department of Haematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Haematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Dexiang
authors.initials: D
authors.lastname: Ji
authors.affiliation: Department of Haematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Song
authors.affiliation: Department of Haematology, Jiangxi Academy of Medical Science, Nanchang 330006, China.
authors.forename: Liya
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Haematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.affiliation: Department of Haematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
mesh_terms: D015120:6-Aminonicotinamide / Q000494:pharmacology; D000077716:Afatinib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D005947:Glucose / Q000378:metabolism; D006801:Humans; D055442:Metabolome / Q000187:drug effects; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D015120:6-Aminonicotinamide; D000077716:Afatinib; D066246:ErbB Receptors; D000077156:Gefitinib; D005947:Glucose; D010100:Oxygen; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C508053:ERBB2 protein, human; C482119:BRAF protein, human