title: Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance.
abstract: Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells.
authors.affiliation: Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Gurden
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom. Division of Structural Biology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Westwood
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Amir
authors.initials: A
authors.lastname: Faisal
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Naud
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Kwai-Ming J
authors.initials: KM
authors.lastname: Cheung
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Craig
authors.initials: C
authors.lastname: McAndrew
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Wood
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Schmitt
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Grace
authors.initials: G
authors.lastname: Mak
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burke
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Swen
authors.initials: S
authors.lastname: Hoelder
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom. Division of Structural Biology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rob L M
authors.initials: RL
authors.lastname: Van Montfort
authors.affiliation: Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom. Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom. Spiros.Linardopoulos@icr.ac.uk.
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D045325:HCT116 Cells; D057809:HEK293 Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D018797:Cell Cycle Proteins; D006574:Heterocyclic Compounds, 2-Ring; C555141:N-(2,6-diethylphenyl)-1-methyl-8-((4-((1-methylpiperidin-4-yl)carbamoyl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; C586722:tert-butyl 6-(2-chloro-4-(1-methyl-1H-imidazol-5-yl)phenylamino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo(3,2-c)pyridine-1-carboxylate; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human; D000077156:Gefitinib