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Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib.

Terzyan SS, Shen T, Liu X, Huang Q, Teng P, Zhou M, Hilberg F, Cai J, Mooers BHM, Wu J
J Biol Chem 294 10428-10437 (2019)
Related entries: 6ne7, 6nja

Cited: 31 times
EuropePMC logo PMID: 31118272

Abstract

RET is a transmembrane growth factor receptor. Aberrantly activated RET is found in several types of human cancer and is a target for treating RET aberration-associated cancer. Multiple clinically relevant RET protein-tyrosine kinase inhibitors (TKIs) have been identified, but how TKIs bind to RET is unknown except for vandetanib. Nintedanib is a RET TKI that inhibits the vandetanib-resistant RET(G810A) mutant. Here, we determined the X-ray co-crystal structure of RET kinase domain-nintedanib complex to 1.87 Å resolution and a RET(G810A) kinase domain crystal structure to 1.99 Å resolution. We also identified a vandetanib-resistant RET(L881V) mutation previously found in familial medullary thyroid carcinoma. Drug-sensitivity profiling of RET(L881V) revealed that it remains sensitive to nintedanib. The RET-nintedanib co-crystal structure disclosed that Leu-730 in RET engages in hydrophobic interactions with the piperazine, anilino, and phenyl groups of nintedanib, providing a structural basis for explaining that the p.L730V mutation identified in nine independently isolated cell lines resistant to nintedanib. Comparisons of RET-nintedanib, RET(G810A), and RET-vandetanib crystal structures suggested that the solvent-front Ala-810 makes hydrophobic contacts with a methyl group and aniline in nintedanib and blocks water access to two oxygen atoms of vandetanib, resulting in an energetic penalty for burying polar groups. Of note, even though the p.L881V mutation did not affect sensitivity to nintedanib, RET(L881V) was resistant to nintedanib analogs lacking a phenyl group. These results provide structural insights into resistance of RET mutants against the TKIs nintedanib and vandetanib.

Articles - 6nec mentioned but not cited (11)

  1. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Subbiah V, Shen T, Terzyan SS, Liu X, Hu X, Patel KP, Hu M, Cabanillas M, Behrang A, Meric-Bernstam F, Vo PTT, Mooers BHM, Wu J. Ann Oncol 32 261-268 (2021)
  2. Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib. Terzyan SS, Shen T, Liu X, Huang Q, Teng P, Zhou M, Hilberg F, Cai J, Mooers BHM, Wu J. J Biol Chem 294 10428-10437 (2019)
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  5. Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors. Kalinichenko E, Faryna A, Bozhok T, Panibrat A. Int J Mol Sci 22 12738 (2021)
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Reviews citing this publication (13)

  1. Advances in Targeting RET-Dependent Cancers. Subbiah V, Cote GJ. Cancer Discov 10 498-505 (2020)
  2. The importance of the RET gene in thyroid cancer and therapeutic implications. Salvatore D, Santoro M, Schlumberger M. Nat Rev Endocrinol 17 296-306 (2021)
  3. Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective. Yang Y, Li S, Wang Y, Zhao Y, Li Q. Signal Transduct Target Ther 7 329 (2022)
  4. The Interactions of Nintedanib and Oral Anticoagulants-Molecular Mechanisms and Clinical Implications. Grześk G, Woźniak-Wiśniewska A, Błażejewski J, Górny B, Wołowiec Ł, Rogowicz D, Nowaczyk A. Int J Mol Sci 22 E282 (2020)
  5. Targeting Rearranged during Transfection in Cancer: A Perspective on Small-Molecule Inhibitors and Their Clinical Development. Saha D, Ryan KR, Lakkaniga NR, Acharya B, Garcia NG, Smith EL, Frett B. J Med Chem 64 11747-11773 (2021)
  6. RET kinase alterations in targeted cancer therapy. Liu X, Hu X, Shen T, Li Q, Mooers BHM, Wu J. Cancer Drug Resist 3 472-481 (2020)
  7. RET kinase inhibitors for RET-altered thyroid cancers. Vodopivec DM, Hu MI. Ther Adv Med Oncol 14 17588359221101691 (2022)
  8. Pralsetinib: chemical and therapeutic development with FDA authorization for the management of RET fusion-positive non-small-cell lung cancers. Ali F, Neha K, Chauhan G. Arch Pharm Res 45 309-327 (2022)
  9. Targeted therapy of RET fusion-positive non-small cell lung cancer. Shen Z, Qiu B, Li L, Yang B, Li G. Front Oncol 12 1033484 (2022)
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Articles citing this publication (7)



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