ECB-ART-49329
Cancers (Basel)
2021 Feb 09;134:. doi: 10.3390/cancers13040699.
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Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer.
Smolle E
,
Taucher V
,
Lindenmann J
,
Jost PJ
,
Pichler M
.
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Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC.
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Figure 1. The EML4-ALK fusion gene. The N-terminal portion of EML4 is fused, containing the main region of EML4-ALK, i.e., the echinoderm microtubule-associated protein-like protein (HELP) domain, and part of the WD-repeat region to the intracellular region of ALK, which contains the tyrosine kinase domain. The transmembrane (TM) domain is not part of the final fusion product. Reproduced from Golding et al. [11]. |
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Figure 2. The EML4-ALK protein complex interaction model, as constructed using a tandem affinity purification approach with consecutive mass spectrometry. Reproduced from Golding et al. [11]. |
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