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

Terzyan, Simon; Shen, Tao; Li, Xuan; Huang, Qingling; Teng, P. K.; Zhou, Mi; Hilberg, Frank; Cai, Jianfeng; Mooers, Blaine H. M.; Wu, Jie

doi:10.1074/jbc.ra119.007682

Cited by 45 publications

(54 citation statements)

References 40 publications

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“…Although there have been single-case reports of RET V804M and RET S904F mutations conferring resistance to the MKI vandetanib in patients, 18,19 and we recently reported the ability of selpercatinib to overcome both hereditary and acquired RET V804M gatekeeper mutation in patients, 17,18 this report of G810 solvent front mutations provides the first description of acquired, "ontarget" resistance to selective RET inhibition in patients (previous studies have identified RET solvent front mutations in preclinical models of resistance to MKIs, [22][23][24] but not in patients and not with selective RET TKIs). A limitation of this study is the relatively small cohort of patients with acquired resistance studied, and it is likely that activation of bypass signaling and other mechanisms of resistance to selective RET TKIs will be identified through analyses of additional progression biopsies.…”

Section: Discussionmentioning

confidence: 82%

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

Solomon

Tan

Lin

et al. 2020

Journal of Thoracic Oncology

213

160

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Section: Discussionmentioning

confidence: 82%

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

Solomon

Tan

Lin

et al. 2020

Journal of Thoracic Oncology

213

160

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“…1,7 Structurally, this is partly because these TKIs are known or predicted to occupy both the front and back drug-binding clefts of the RET kinase domain by going through the gate that separates these two clefts. [8][9][10][11][12] Selpercatinib [13][14][15] and pralsetinib 16 are two highly selective and potent RET TKIs. Recently, selpercatinib received the United States Food and Drug Administration (FDA) approval for treating metastatic RET fusion-positive nonsmall-cell lung cancer (NSCLC), advanced/metastatic RET-altered medullary thyroid cancer (MTC), and papillary thyroid carcinoma, while pralsetinib was approved by the FDA for treating RET fusion-positive NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations

et al. 2021

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Background: Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes. Patients and methods: Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation. Results: RET G810C/S mutations at the solvent front and RET Y806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RET M918T/V804M/L , who initially responded to selpercatinib and developed resistance. RET G810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RETselpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft. Conclusions: RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.

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“…Active site residues, which exist in the hydrophobic region (highlighted as lines in the Figure 1 b), appear to form hydrophobic interactions with the highly potent compound 25 . The part of ligand with an isoxazole moiety was docked inside the hydrophobic pocket, which formed hydrophobic interactions with residues Leu730, Ala756, Val804, and Tyr806, among which Val804 is a gatekeeper residue [ 21 ]. The fused ring was also in a close proximity of hydrophobic residues Ala807, Gly810, Ser811, and Leu881, forming hydrophobic interactions.…”

Section: Resultsmentioning

confidence: 99%

Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors

2021

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RET (rearranged during transfection) kinase, one of the receptor tyrosine kinases, plays a crucial role in the development of the human nervous system. It is also involved in various cell signaling networks responsible for the normal cell division, growth, migration, and survival. Previously reported clinical studies revealed that deregulation or aberrant activation of RET signaling can cause several types of human cancer. For example, medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia (MEN2A, MEN2B) occur due to sporadic mutation or germline RET mutation. A number of RET kinase inhibitors have been approved by the FDA for the treatment of cancer, such as cabozantinib, vandetanib, lenvatinib, and sorafenib. However, each of these drugs is a multikinase inhibitor. Hence, RET is an important therapeutic target for cancer drug design. In this work, we have performed various molecular modelling studies, such as molecular docking and dynamics simulation for the most active compound of the pyrazole series as RET kinase inhibitors. Furthermore, molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) free energy calculation and 3-dimensional quantitative structure–activity relationship (3D-QSAR) were performed using g_mmpbsa and SYBYL-X 2.1 package. The results of this study revealed the crucial binding site residues at the active site of RET kinase and contour map analysis showed important structural characteristics for the design of new highly active inhibitors. Therefore, we have designed ten RET kinase inhibitors, which showed higher inhibitory activity than the most active compound of the series. The results of our study provide insights to design more potent and selective RET kinase inhibitors.

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

Cited by 45 publications

References 40 publications

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations

Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors

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