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

Gurden MD, Westwood IM, Faisal A, Naud S, Cheung KM, McAndrew C, Wood A, Schmitt J, Boxall K, Mak G, Workman P, Burke R, Hoelder S, Blagg J, Van Montfort RL, Linardopoulos S
Cancer Res 75 3340-54 (2015)
Related entries: 5ap0, 5ap1, 5ap3, 5ap4, 5ap5, 5ap6, 5ap7

Cited: 16 times
EuropePMC logo PMID: 26202014

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.

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  2. Single-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon Cancer. Vasudevan A, Baruah PS, Smith JC, Wang Z, Sayles NM, Andrews P, Kendall J, Leu J, Chunduri NK, Levy D, Wigler M, Storchová Z, Sheltzer JM. Dev Cell 52 413-428.e6 (2020)
  3. TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability. Choi M, Min YH, Pyo J, Lee CW, Jang CY, Kim JE. Br J Pharmacol 174 1810-1825 (2017)
  4. Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy. Faisal A, Mak GWY, Gurden MD, Xavier CPR, Anderhub SJ, Innocenti P, Westwood IM, Naud S, Hayes A, Box G, Valenti MR, De Haven Brandon AK, O'Fee L, Schmitt J, Woodward HL, Burke R, vanMontfort RLM, Blagg J, Raynaud FI, Eccles SA, Hoelder S, Linardopoulos S. Br J Cancer 116 1166-1176 (2017)
  5. Structural basis of reversine selectivity in inhibiting Mps1 more potently than aurora B kinase. Hiruma Y, Koch A, Dharadhar S, Joosten RP, Perrakis A. Proteins 84 1761-1766 (2016)
  6. Aurora B prevents premature removal of spindle assembly checkpoint proteins from the kinetochore: A key role for Aurora B in mitosis. Gurden MD, Anderhub SJ, Faisal A, Linardopoulos S. Oncotarget 9 19525-19542 (2018)
  7. Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures. Hiruma Y, Koch A, Hazraty N, Tsakou F, Medema RH, Joosten RP, Perrakis A. J Biol Chem 292 14496-14504 (2017)
  8. Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer. Kaserer T, Blagg J. Cell Chem Biol 25 1359-1371.e2 (2018)
  9. LAHMA: structure analysis through local annotation of homology-matched amino acids. van Beusekom B, Damaskos G, Hekkelman ML, Salgado-Polo F, Hiruma Y, Perrakis A, Joosten RP. Acta Crystallogr D Struct Biol 77 28-40 (2021)
  10. A crystal structure of the human protein kinase Mps1 reveals an ordered conformation of the activation loop. Roorda JC, Joosten RP, Perrakis A, Hiruma Y. Proteins 87 348-352 (2019)
  11. How Far Are We from the Rapid Prediction of Drug Resistance Arising Due to Kinase Mutations? Erguven M, Karakulak T, Diril MK, Karaca E. ACS Omega 6 1254-1265 (2021)
  12. Insights into Resistance Mechanisms of Inhibitors to Mps1 C604Y Mutation via a Comprehensive Molecular Modeling Study. Chen Y, Yu W, Jiang CC, Zheng JG. Molecules 23 E1488 (2018)


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