Unraveling the Impact of Intratumoral Heterogeneity on EGFR Tyrosine Kinase Inhibitor Resistance in EGFR-Mutated NSCLC

Abstract

The advent of tyrosine kinase inhibitors (TKIs) for treating epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) has been a game changer in lung cancer therapy. However, patients often develop resistance to the drugs within a few years. Despite numerous studies that have explored resistance mechanisms, particularly in regards to collateral signal pathway activation, the underlying biology of resistance remains largely unknown. This review focuses on the resistance mechanisms of EGFR-mutated NSCLC from the standpoint of intratumoral heterogeneity, as the biological mechanisms behind resistance are diverse and largely unclear. There exist various subclonal tumor populations in an individual tumor. For lung cancer patients, drug-tolerant persister (DTP) cell populations may have a pivotal role in accelerating the evolution of tumor resistance to treatment through neutral selection. Cancer cells undergo various changes to adapt to the new tumor microenvironment caused by drug exposure. DTP cells may play a crucial role in this adaptation and may be fundamental in mechanisms of resistance. Intratumoral heterogeneity may also be precipitated by DNA gains and losses through chromosomal instability, and the role of extrachromosomal DNA (ecDNA) may play an important role. Significantly, ecDNA can increase oncogene copy number alterations and enhance intratumoral heterogeneity more effectively than chromosomal instability. Additionally, advances in comprehensive genomic profiling have given us insights into various mutations and concurrent genetic alterations other than EGFR mutations, inducing primary resistance in the context of tumor heterogeneity. Understanding the mechanisms of resistance is clinically crucial since these molecular interlayers in cancer-resistance mechanisms may help to devise novel and individualized anticancer therapeutic approaches.

An integrated strategy of UPLC-Q-TOF-MS analysis, network pharmacology, and molecular docking to explore the chemical constituents and mechanism of Zixue Powder against febrile seizures

“…While AKT1 (PDB ID: 3O96 ) exhibited the excellent binding interaction with most of the tested compounds, which was considered as the essential protein in anti-inflammation [ 53 ]. Meanwhile, compound 44 bound to EGFR (PDB ID: 2GS6 ) with the score at −62.32 kcal/mol, which was the key protein of the EGFR tyrosine kinase inhibitor pathway [ 54 ], showing the strong interaction comparing with the original ligand (score at −77.23 kcal/mol). Therefore, take compound 44 docked with AKT1 (PDB ID: 3O96 ) as an example.…”

Advancements in Focal Amplification Detection in Tumor/Liquid Biopsies and Emerging Clinical Applications

“…DMs are also involved in determining intratumoral heterogeneity, which is crucial to causing drug resistance and a shorter overall survival in cancer patients [ 20 ] for two main reasons. The former is related to differences in the internal amplicon architecture.…”