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

• Published in: Cancers Vol. 11; no. 7; p. 923
• Main Authors: Santoni-Rugiu, Eric, Melchior, Linea C, Urbanska, Edyta M, Jakobsen, Jan N, Stricker, Karin de, Grauslund, Morten, Sørensen, Jens B
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.07.2019; MDPI
• Subjects: Binding sites; Cloning; EGFR-mutated non-small cell lung cancer; EGFR-TKI; Epidermal growth factor; Epidermal growth factor receptors; intrinsic resistance; Kinases; Lung cancer; Medical prognosis; Metastasis; Mutation; Non-small cell lung carcinoma; Patients; Proteins; resistance mechanisms; Review; Small cell lung carcinoma; Tyrosine kinase inhibitors; EGFR-TKI; EGFR-mutated non-small cell lung cancer; intrinsic resistance; resistance mechanisms
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers11070923

Activating mutations in the 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 -mutated ( M+) 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 M+ 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 or by -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.