Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.

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Transformation from non-small cell lung cancer to small cell lung cancer: A report of clinicopathological characteristics and prognoses.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15084 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15084-e15084

Author(s):

Jun Wang ◽

Qing Liu ◽

Yanhong Shang ◽

Linlin Xiao ◽

Ran Huo

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Clinicopathological Characteristics ◽

Small Cell ◽

Line Treatment ◽

Small Cell Lung ◽

First Line ◽

Egfr Tkis ◽

First Line Treatment

e15084 Background: The transformation to small cell lung cancer (SCLC) is one of the mechanisms of drug resistance in non-small cell lung cancer (NSCLC). However, there are few reports on it. The study aims to analyze the clinicopathological characteristics of the patients, to explore the transformation factors and reasonable treatment strategy for them. Methods: A total of 9 patients with pathologically diagnosed NSCLC transformed into SCLC after first-line or multi-line treatment were involved in the study. Results: Among the 9 patients, there were 8 adenocarcinomas (ADC) and 1 squamous cell carcinoma (SCC), 7 of them were non-smokers. Epidermal growth factor receptor (EGFR) mutations were present in all ADC patients, including 7 with exon19 deletion (87.5%) and 1 with exon21 mutation (12.5%). All of them received EGFR tyrosine kinase inhibitors (TKIs) before the transformation, and the median transformation time was 19.5 months (95% CI, 14.1-32.7months). After first-line chemotherapy with paclitaxel and cisplatin, one SCC patient transformed to SCLC within 5 months. EGFR mutation was still maintained in 6 ADC patients when transformation occurred, of which 2 patients had a new TP53 mutation and 1 had RB1 gene mutation. Serum tumor markers were monitored in 6 patients, of them, progastrin releasing peptide (Pro-GRP) increased apparently at the time of disease progression in 5 patients, and neuron-specific enolase (NSE) also increased in 3 patients. This phenomenon occurred three to six months earlier than the transformation. The median survival time (MST) was 37 months from the initial diagnosis of NSCLC and 13 months after transformation. The median progression-free survival (mPFS) was only 2 months for those treated with chemotherapy (CT) after transformation, whereas 6 months treated with CT combined with TKIs as the first-line treatment. Three patients who received chemotherapy combined with programmed death receptor-1 (PD-1) inhibitor after multi-line therapy underwent progress within 2 months, nevertheless, 1 patient treated with the EP regimen combined with pembrolizumab as the first line treatment after transformation had a PFS of 12 months. After re-progression, the patients got another PFS of 5 months with a pemetrexed-platinum combined with atezolizumab. Conclusions: Phenotypic transformation is one of the mechanisms of drug resistance for NSCLC patients, especially for those with EFGR exon19 deletion received EGFR-TKIs. Tumor heterogeneity, TP53 gene and Rb gene mutation may be responsible for the transformation. The serum Pro-GRP over expression could as an early predictor of transformation. Classical chemotherapy is ineffective after SCLC transformation patients who still have sensitive mutation, it might be suitable to combine with EGFR-TKIs. The early application of immunotherapy could be attempted, but still needs to be explored further.

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