5AP4

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

Summary for 5AP4

• Entry DOI: 10.2210/pdb5ap4/pdb
• Related: 5AP0 5AP1 5AP2 5AP3 5AP5 5AP6 5AP7
• Descriptor: DUAL SPECIFICITY PROTEIN KINASE TTK, 6-{[3-(cyanomethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl]amino}-2-(cyclohexylamino)pyridine-3-carbonitrile, 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL, ... (5 entities in total)
• Functional Keywords: transferase, mps1, protein kinase, mitosis, drug resistance
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 37337.62

Authors

Gurden, M.D.,Westwood, I.M.,Faisal, A.,Naud, S.,Cheung, K.J.,McAndrew, C.,Wood, A.,Schmitt, J.,Boxall, K.,Mak, G.,Workman, P.,Burke, R.,Hoelder, S.,Blagg, J.,van Montfort, R.L.M.,Linardopoulos, S. (deposition date: 2015-09-14, release date: 2015-09-23, Last modification date: 2024-01-10)

Primary citation

Gurden, M.D.,Westwood, I.M.,Faisal, A.,Naud, S.,Cheung, K.J.,Mcandrew, C.,Wood, A.,Schmitt, J.,Boxall, K.,Mak, G.,Workman, P.,Burke, R.,Hoelder, S.,Blagg, J.,Van Montfort, R.L.M.,Linardopoulos, S.
Naturally Occurring Mutations in the Mps1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance.
Cancer Res., 75:3340-, 2015

PubMed 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.

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

Experimental method

X-RAY DIFFRACTION (2.85 Å)