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Open AccessReview

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

1
Department of Pathology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark
2
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark
3
Department of Oncology and Palliative Units, Zealand University Hospital, DK-4700 Næstved, Denmark
4
Department of Clinical Genetics and Pathology, Skåne University Hospital, SE-221 85 Lund, Sweden
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(7), 923; https://doi.org/10.3390/cancers11070923
Received: 19 April 2019 / Revised: 25 June 2019 / Accepted: 25 June 2019 / Published: 1 July 2019
Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them. View Full-Text
Keywords: EGFR-mutated non-small cell lung cancer; EGFR-TKI; intrinsic resistance; resistance mechanisms EGFR-mutated non-small cell lung cancer; EGFR-TKI; intrinsic resistance; resistance mechanisms
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Santoni-Rugiu, E.; Melchior, L.C.; Urbanska, E.M.; Jakobsen, J.N.; de Stricker, K.; Grauslund, M.; Sørensen, J.B. Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance. Cancers 2019, 11, 923.

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