Abstract
Molecular targeted medicine has progressed in non-small cell lung cancer in recent years, and acquired resistance to molecular targeted therapy has become a major problem. Several mechanisms of acquired resistance have been described, such as secondary mutation of targeted genes, bypass pathway activation, and phenotypic transformation, including epithelial-mesenchymal transition and small cell lung cancer transformation. However, detailed mechanisms and the strategy to overcome the resistance have yet to be clarified thoroughly. In this study, we established a squamous lung cancer cell line with acquired resistance to FGFR tyrosine kinase inhibitor in vitro and identified achaete-scute family bHLH transcription factor 1 (ASCL1) overexpression as a mechanism of the resistance to tyrosine kinase inhibitor treatment.
We identified LK-2 as a squamous cell lung cancer cell line that is highly sensitive to FGFR tyrosine kinase inhibitor AZD4547, which is currently evaluated in clinical trial in squamous cell lung cancer, and established its resistant clone in vitro by exposing gradually increasing concentration of AZD4547. The resistant clone was morphologically more round-shaped and expressed ASCL1 significantly higher than the original LK-2 in a microarray analysis, but did not have additional mutations in putative genes responsible for resistance in RNA-sequencing. ASCL1 inhibition with shRNA lentivirus did not restore the sensitivity to AZD4547, but significantly suppressed the growth of the resistant clone compared to the original LK-2. Cyclin A1 (CCNA1) expression was also increased in the resistant clone and was regulated by ASCL1. CCNA1 inhibition also suppressed the growth of the resistant clone.
These results suggest that ASCL1 was one of the key molecules for the acquired resistance to tyrosine kinase inhibitor therapy, and considering the evidence that ASCL1 is a master regulator of small cell lung cancer-like phenotype, it may be related to small cell lung cancer transformation as a mechanism of the resistance. ASCL1 and its downstream molecule CCNA1 may be candidates to overcome the resistance to tyrosine kinase inhibitor therapy.
Citation Format: Yosuke Amano, Takahiro Ando, Keita Maemura, Toshio Sakatini, Mitsuhiro Sunohara, Kosuke Watanabe, Hidenori Kage. Exposure of AZD4547 FGFR-TKI to a lung squamous carcinoma cell line induces resistance by small cell lung cancer-like transformation associated with ASCL1 [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B22.
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