Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors

Monika Davare, Nadeem A. Vellore, Jacob P. Wagner, Christopher A. Eide, James R. Goodman, Alexander Drilon, Michael W. Deininger, Thomas O'Hare, Brian Druker

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1- and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib's dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1- and ALK-driven NSCLC and other malignancies.

Original languageEnglish (US)
Pages (from-to)E5381-E5390
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number39
DOIs
StatePublished - Sep 29 2015

Fingerprint

Protein-Tyrosine Kinases
Phosphotransferases
Non-Small Cell Lung Carcinoma
anaplastic lymphoma kinase
Drug Design
United States Food and Drug Administration
Molecular Dynamics Simulation
Catalytic Domain
Neoplasms
Binding Sites
Mutation

Keywords

  • ALK
  • Inhibitor
  • Kinase
  • ROS1
  • Structural modelling

ASJC Scopus subject areas

  • General

Cite this

Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors. / Davare, Monika; Vellore, Nadeem A.; Wagner, Jacob P.; Eide, Christopher A.; Goodman, James R.; Drilon, Alexander; Deininger, Michael W.; O'Hare, Thomas; Druker, Brian.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 39, 29.09.2015, p. E5381-E5390.

Research output: Contribution to journalArticle

Davare, Monika ; Vellore, Nadeem A. ; Wagner, Jacob P. ; Eide, Christopher A. ; Goodman, James R. ; Drilon, Alexander ; Deininger, Michael W. ; O'Hare, Thomas ; Druker, Brian. / Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 39. pp. E5381-E5390.
@article{1c266a5d5dc64bc19ef1d0113785fdea,
title = "Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors",
abstract = "Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1- and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib's dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1- and ALK-driven NSCLC and other malignancies.",
keywords = "ALK, Inhibitor, Kinase, ROS1, Structural modelling",
author = "Monika Davare and Vellore, {Nadeem A.} and Wagner, {Jacob P.} and Eide, {Christopher A.} and Goodman, {James R.} and Alexander Drilon and Deininger, {Michael W.} and Thomas O'Hare and Brian Druker",
year = "2015",
month = "9",
day = "29",
doi = "10.1073/pnas.1515281112",
language = "English (US)",
volume = "112",
pages = "E5381--E5390",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "39",

}

TY - JOUR

T1 - Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors

AU - Davare, Monika

AU - Vellore, Nadeem A.

AU - Wagner, Jacob P.

AU - Eide, Christopher A.

AU - Goodman, James R.

AU - Drilon, Alexander

AU - Deininger, Michael W.

AU - O'Hare, Thomas

AU - Druker, Brian

PY - 2015/9/29

Y1 - 2015/9/29

N2 - Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1- and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib's dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1- and ALK-driven NSCLC and other malignancies.

AB - Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1- and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib's dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1- and ALK-driven NSCLC and other malignancies.

KW - ALK

KW - Inhibitor

KW - Kinase

KW - ROS1

KW - Structural modelling

UR - http://www.scopus.com/inward/record.url?scp=84942860475&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942860475&partnerID=8YFLogxK

U2 - 10.1073/pnas.1515281112

DO - 10.1073/pnas.1515281112

M3 - Article

VL - 112

SP - E5381-E5390

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 39

ER -