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Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance

DOI: 10.1158/0008-5472.CAN-14-3272 DOI Help
PMID: 26202014 PMID Help

Authors: M. D. Gurden (The Institute of Cancer Research) , Isaac Westwood (Institute of Cancer Research, Cancer Research UK) , A. Faisal (The Institute of Cancer Research) , S. Naud (The Institute of Cancer Research) , K. M. J. Cheung (The Institute of Cancer Research) , C. Mcandrew (The Institute of Cancer Research) , A. Wood (The Institute of Cancer Research) , J. Schmitt (The Institute of Cancer Research) , K. Boxall (The Institute of Cancer Research) , G. Mak (The Institute of Cancer Research) , P. Workman (The Institute of Cancer Research) , R. Burke (The Institute of Cancer Research) , S. Hoelder (The Institute of Cancer Research) , J. Blagg (The Institute of Cancer Research) , Rob Van Montfort (Institute of Cancer Research) , S. Linardopoulos (The Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cancer Research , VOL 75 (16) , PAGES 3340 - 3354

State: Published (Approved)
Published: August 2015
Diamond Proposal Number(s): 8015 , 10088

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.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography