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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Published on: November 22, 2021

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

Eric Santoni-Rugiu¹, Linea C Melchior², Edyta M Urbanska³

¹Department of Pathology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark. eric.santoni-rugiu.02@regionh.dk.

|July 4, 2019

Abstract:

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.

Insights

Activating mutations in the epidermal growth factor receptor (EGFR) gene drive non-small cell lung cancer (NSCLC). Intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs) in NSCLC arises from complex genetic and phenotypic factors, necessitating comprehensive profiling.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Activating mutations in the epidermal growth factor receptor (EGFR) gene are early drivers in a subset of non-small cell lung cancer (NSCLC) patients, conferring sensitivity to EGFR-tyrosine kinase inhibitors (TKIs).
Despite initial responses, most advanced EGFR-mutated (EGFRM+) NSCLCs develop acquired resistance to EGFR-TKIs.
A significant proportion (20-30%) of patients exhibit intrinsic resistance, responding poorly or not at all to EGFR-TKIs, with mechanisms less understood than acquired resistance.

Purpose of the Study:

To comprehensively review and describe the identified mechanisms of intrinsic resistance to EGFR-TKIs in advanced EGFR-mutated NSCLC.
To compare and contrast intrinsic resistance mechanisms with those of acquired resistance.
To highlight the importance of pre-treatment molecular profiling for identifying intrinsically resistant cases and guiding combinatorial targeted strategies.

Main Methods:

Comprehensive review of existing literature on EGFR-TKI resistance mechanisms in NSCLC.
Analysis of molecular-pathological profiling data from advanced EGFRM+ NSCLC at baseline.
Synthesis of findings from preclinical experiments corroborating identified resistance mechanisms.

Main Results:

Intrinsic resistance to EGFR-TKIs in NSCLC can stem from EGFR-intrinsic mechanisms or EGFR-independent processes, including genetic, phenotypic, and functional tumor alterations.
Multiple co-existing mechanisms contribute to intrinsic resistance, differing from or overlapping with acquired resistance pathways.
Understanding these mechanisms is crucial for differentiating intrinsic from acquired resistance across various EGFR-TKI generations.

Conclusions:

Intrinsic resistance to EGFR-TKIs in NSCLC is multifactorial, involving complex genetic and phenotypic tumor characteristics.
Pre-treatment molecular profiling is essential for identifying patients with intrinsic TKI resistance.
Developing combinatorial targeted therapies based on comprehensive profiling is necessary to overcome intrinsic resistance and improve treatment outcomes in NSCLC.

Read full analysis

Keywords:

EGFR-TKI EGFR-mutated non-small cell lung cancer intrinsic resistance resistance mechanisms

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