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

Kenichi Suda, Isao Murakami, Kazuko Sakai, Hiroshi Mizuuchi, Shigeki Shimizu, Katsuaki Sato, Kenji Tomizawa, Shuta Tomida, Yasushi Yatabe, Kazuto Nishio, Tetsuya Mitsudomi, Kenichi Suda, Isao Murakami, Kazuko Sakai, Hiroshi Mizuuchi, Shigeki Shimizu, Katsuaki Sato, Kenji Tomizawa, Shuta Tomida, Yasushi Yatabe, Kazuto Nishio, Tetsuya Mitsudomi

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.

Conflict of interest statement

T.M. has received honoraria from AstraZeneca, Chugai, BoehlingerIngelheim, and Roche, played an advisory role for AstraZeneca, Chugai, Boehlinger-Ingelheim, Roche, and Clovis Oncology, and has received research funding from AstraZeneca, Chugai and Takeda. All other authors declare that they have no conflict of interest.

Figures

Figure 1. Anatomical and pathological examination of…
Figure 1. Anatomical and pathological examination of gefitinib-refractory metastatic lesions of the patient.
(A) Schema of the metastatic lesions available. There were no viable tumour cells in the primary lung tumour. Red lesions indicate adenocarcinoma histology, and all adenocarcinoma lesions harboured the T790M mutation. Blue lesions indicate SCLC histology, and none of the SCLC lesions had the T790M mutation. One retroperitoneum lymph node possessed both the adenocarcinoma component with a T790M mutation and the SCLC component, independently. (B) Macroscopically, there were two types of tumours in the liver. Lesions in the right lobe consisted of adenocarcinoma histology. Lesions in the left lobe showed SCLC histology. (C) Detail of the retroperitoneum lymph node that possessed both the adenocarcinoma and SCLC components is shown.

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