Abstract
Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.
Highlights
Lung cancers with epidermal growth factor receptor (EGFR) gene mutation account for ~40% of lung adenocarcinomas in East Asians and ~20% in Caucasians and African Americans[1]
Among 16 autopsy cases that met the clinical definition of acquired resistance to EGFR-TKIs16, one patient developed small cell lung cancer (SCLC) transformation
The patient was a 76-yearold female at diagnosis of lung cancer, without smoking history. She was initially treated with platinum-doublet chemotherapy with concurrent radiation for her clinical stage IIIB non-small cell lung cancer (NSCLC)
Summary
Lung cancers with epidermal growth factor receptor (EGFR) gene mutation account for ~40% of lung adenocarcinomas in East Asians and ~20% in Caucasians and African Americans[1]. Gene amplification, ERBB2 gene amplification, overexpression of hepatocyte growth factor, downregulation of PTEN, transformation to small cell lung cancer (SCLC), and epithelial to mesenchymal transition[3,4] Among these resistance mechanisms, relapsed tumours with EGFR T790M secondary mutation and those with SCLC transformation can be treated by “resistance mechanism-based” therapies, such as T790M-specific EGFR-TKIs in clinical trial settings[5] or cytotoxic chemotherapy and radiation for SCLC3. Details of less than 30 patients have been reported in 11 papers so far, based on our literature search[3,6,7,8,9,10,11,12,13,14,15] This acquired resistance mechanism has lately attracted considerable attention as SCLC transformation can be diagnosed by standard pathological examination, and SCLC-specific treatment often shows clinical benefit[3]. It is important to understand inter-tumour heterogeneity of acquired resistance mechanism(s) in a single patient after treatment failure of EGFR-TKIs
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