Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer

• Published in: Scientific reports 2015-09, Vol.5 (1), p.14447-14447, Article 14447
• Main Authors: Suda, Kenichi, Murakami, Isao, Sakai, Kazuko, Mizuuchi, Hiroshi, Shimizu, Shigeki, Sato, Katsuaki, Tomizawa, Kenji, Tomida, Shuta, Yatabe, Yasushi, Nishio, Kazuto, Mitsudomi, Tetsuya
• Format: Article
• Language: English
• Subjects: 692/308/575; 692/4028/67/1612/1350; Aged; Amino Acid Substitution; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Autopsy; Cell Transformation, Neoplastic - genetics; Codon; DNA Copy Number Variations; Drug resistance; Drug Resistance, Neoplasm - genetics; Epidermal growth factor; Epidermal growth factor receptors; Female; Genetic transformation; Humanities and Social Sciences; Humans; Kinases; Lesions; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lungs; multidisciplinary; Mutation; Neoplasm Metastasis; Neoplasm Staging; p53 Protein; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Proto-Oncogene Proteins c-met - genetics; PTEN protein; Receptor, Epidermal Growth Factor - genetics; Science; Small cell lung carcinoma; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - pathology; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep14447

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.