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Hope and Disappointment: Covalent Inhibitors to Overcome Drug Resistance in Non-Small Cell Lung Cancer.

ABSTRACT: In the last five years, the detailed understanding of how to overcome T790M drug resistance in non-small cell lung cancer (NSCLC) has culminated in the development of a third-generation of covalent EGFR inhibitors with excellent clinical outcomes. However, the emergence of a newly discovered acquired drug resistance challenges the concept of small molecule targeted cancer therapy in NSCLC.

SUBMITTER: Engel J

PROVIDER: S-EPMC4716607 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Hope and Disappointment: Covalent Inhibitors to Overcome Drug Resistance in Non-Small Cell Lung Cancer.

Engel Julian J Lategahn Jonas J Rauh Daniel D

ACS medicinal chemistry letters 20151218 1

In the last five years, the detailed understanding of how to overcome T790M drug resistance in non-small cell lung cancer (NSCLC) has culminated in the development of a third-generation of covalent EGFR inhibitors with excellent clinical outcomes. However, the emergence of a newly discovered acquired drug resistance challenges the concept of small molecule targeted cancer therapy in NSCLC. ...[more]

PMID: 26819655

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Project description:Background and objectiveAnaplastic lymphoma kinase (ALK) rearrangements are detected in 3-7% of advanced non-small cell lung cancer (NSCLC). There are currently 5 U.S Food and Drug Administration (FDA)-approved ALK tyrosine kinase inhibitors (TKIs) for the treatment of patients with ALK-positive lung cancer in the advanced/metastatic disease setting. Despite these advances, most patients with ALK-positive lung cancer who are treated with ALK TKI therapy ultimately experience disease progression due to various mechanisms of drug resistance. In this review, we discuss strategies to address acquired therapeutic resistance to ALK inhibition, novel agents and combinatorial strategies in development for both on and off-target resistance, and some emerging approaches to prolong response to ALK inhibitors.MethodsWe performed a search of peer-reviewed literature in the English language, conference abstracts, and trial registrations from the MEDLINE (Ovid), Embase (Elsevier), and CENTRAL (Cochrane Library) databases and major international oncology meetings up to August 2022. We then screened for studies describing interventions to overcome ALK resistance based on review of each title and abstract.Key content and findingsFor patients with oligo-progression, treatment may include maintaining the same systemic treatment beyond progression while adding local therapies to progressing lesions. Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4th generation TKIs (TPX-0131, NVL-655) and proteolysis-targeting chimeras (PROTACs) currently in development. While for those patients who develop tumor progression due to off-target (ALK independent) resistance, options may include combination therapies targeting ALK and other downstream or parallel pathways, novel antibody drug conjugates, or combinations of ALK inhibitors with chemotherapy and immunotherapy. Lastly, other potential strategies being explored in the clinic include circulating tumor DNA (ctDNA) surveillance to monitor for molecular mediators of drug resistance prior to frank progression on imaging studies and utilization of ALK TKIs in the adjuvant and neoadjuvant settings.ConclusionsStrategies to overcome resistance to currently available ALK inhibitors are urgently needed. Given the variety of resistance mechanisms, tailormade approaches are required for disease control.

Dataset Information

Hope and Disappointment: Covalent Inhibitors to Overcome Drug Resistance in Non-Small Cell Lung Cancer.

Publications

Hope and Disappointment: Covalent Inhibitors to Overcome Drug Resistance in Non-Small Cell Lung Cancer.

Similar Datasets

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