Acquired Resistance to Crizotinib from a Mutation in <i>CD74</i>–<i>ROS1</i>

Awad, Mark M.; Katayama, Ryohei; McTigue, Michele; Liu, Wei; Deng, Yaoyao; Brooun, Alexei; Friboulet, Luc; Huang, Donghui; Falk, Matthew D.; Timofeevski, Sergei; Wilner, Keith D.; Lockerman, Elizabeth L.; Khan, Tahsin M.; Mahmood, Sajid; Gainor, Justin F.; Digumarthy, Subba R.; Stone, James R.; Mino‐Kenudson, Mari; Christensen, James G.; Iafrate, A. John; Engelman, Jeffrey A.; Shaw, Alice T.

doi:10.1056/nejmoa1215530

Cited by 354 publications

(274 citation statements)

References 24 publications

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“…A patient with the ROS1-CD74 fusion oncogene initially responded dramatically to two mo of crizotinib treatment but then progressed in the third month. Her tumor was found to have a novel G2032R mutation in the CD74-ROS1 fusion junction that had not been observed before crizotinib treatment [95] . Recently a promising ROS1 inhibitor, foretinib, has been shown to demonstrate efficacy against ROS1-rearranged tumor cells, including crizotinib-resistant cells.…”

Section: Other "Actionable" Molecular Targetsmentioning

confidence: 96%

Review of the current targeted therapies for non-small-cell lung cancer

Nguyen

Neal

Wakelee

2014

WJCO

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The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALKtargeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1 , HER2 , and BRAF are covered as well.The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come. Key words: Lung cancer; Non-small cell lung cancer; Targeted therapies; Epidermal growth factor receptor; Epidermal growth factor receptor; Anaplastic lymphoma kinase; Anaplastic lymphoma kinase; Acquired resistance Core tip: The development of oncogene-directed targeted therapies has significantly changed the treatment of non-small-cell lung cancer. We review the data demonstrating efficacy of small-molecule tyrosine kinase inhibitors against epidermal growth factor receptor, anaplastic lymphoma kinase, ROS1, and other oncogenes. We also discuss the challenge of acquired resistance to these therapies and review promising agents which may overcome resistance.Nguyen KSH, Neal JW, Wakelee H. Review of the current targeted therapies for non-small-cell lung cancer.

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Section: Other "Actionable" Molecular Targetsmentioning

confidence: 96%

Review of the current targeted therapies for non-small-cell lung cancer

Nguyen

Neal

Wakelee

2014

WJCO

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“…For instance, crizotinib concentration needed to achieve 50% enzyme inhibition (Ki) was increased by a factor of 270 for the G2032R mutant kinase as compared with non-mutant ROS1 [34]. Finally, the intermolecular hydrogen bonds in the complex structure were also shown using LIGPLOT to explain the mechanism of crizotinib resistance [35].…”

Section: Docking Studiesmentioning

confidence: 99%

Structural and Functional Impact of G2032r Mutation in Ros1 – A Theoretical Perspective

Kumar

Shanthi

Ramanathan

2017

Asian J Pharm Clin Res

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Objective: Drug resistance is an imperative issue in the treatment of patients with lung cancer. In this work, investigation of the drug resistance mechanism of G2032R mutation in ROS1 is carried out using computational simulation techniques.Methods: Molecular docking and molecular dynamics (MD) simulation approach have been utilized to uncover the mechanism behind crizotinib resistance in ROS1 at a molecular level. Normal mode analysis was carried out using ElNemo server which examines the movements and conformational changes in the protein structure. ArgusLab, PEARLS, and Autodock were employed for the docking analysis, whereas GROMACS package 4.5.3 was used for MD simulation approach. Results:The results from our analysis indicates that wild-type ROS1 (Protein Data Bank Code 3ZBF) could be more crucial for the crizotinib binding as it indicates largest binding affinity, minimum number of H-bonds, and higher flexibility than mutant-type ROS1. Moreover, the theoretical basis for the cause of drug insensitivity is the differences in the electrostatic properties of binding site residues between the wild and mutant ROS1 structures. Our analysis theoretically suggests that E-2027 is a key residue responsible for the ROS1 drug selectivity.Conclusion: Molecular docking and MD simulation results provide an explanation of the resistance caused by G2032R and may give a key clue for the drug design to encounter drug resistance.

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“…One of the simplest types of intrinsic resistance is steric hindrance-when the van der Wall radii of the drug and a kinase residue overlap to block access to the binding site. A recent example is an NSCLC patient with an oncogenic ROS fusion protein who responded to crizotinib but became resistant through a G2032R-mutant variant that directly interferes with crizotinib binding (32). Mutations distal from the ATP-binding site cause drug resistance by different mechanisms.…”

Section: Intrinsic Mechanisms Of Drug Response and Resistancementioning

confidence: 99%

Durability of Kinase-Directed Therapies—A Network Perspective on Response and Resistance

Murray

Miller

2015

Molecular Cancer Therapeutics

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Protein kinase-directed cancer therapies yield impressive initial clinical responses, but the benefits are typically transient. Enhancing the durability of clinical response is dependent upon patient selection, using drugs with more effective pharmacology, anticipating mechanisms of drug resistance, and applying concerted drug combinations. Achieving these tenets requires an understanding of the targeted kinase's role in signaling networks, how the network responds to drug perturbation, and patient-topatient network variations. Protein kinases create sophisticated, malleable signaling networks with fidelity coded into the processes that regulate their presence and function. Robust and reliable signaling is facilitated through network processes (e.g., feedback regulation, and compensatory signaling). The routine use of kinase-directed therapies and advancements in both genomic analysis and tumor cell biology are illuminating the complexity of tumor network biology and its capacity to respond to perturbations. Drug efficacy is attenuated by alterations of the drug target (e.g., steric interference, compensatory activity, and conformational changes), compensatory signaling (bypass mechanisms and phenotype switching), and engagement of other oncogenic capabilities (polygenic disease). Factors influencing anticancer drug response and resistance are examined to define the behavior of kinases in network signaling, mechanisms of drug resistance, drug combinations necessary for durable clinical responses, and strategies to identify mechanisms of drug resistance.

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Acquired Resistance to Crizotinib from a Mutation in CD74–ROS1

Cited by 354 publications

References 24 publications

Review of the current targeted therapies for non-small-cell lung cancer

Review of the current targeted therapies for non-small-cell lung cancer

Structural and Functional Impact of G2032r Mutation in Ros1 – A Theoretical Perspective

Durability of Kinase-Directed Therapies—A Network Perspective on Response and Resistance

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