YES1 and MYC Amplifications as Synergistic Resistance Mechanisms to Different Generation ALK Tyrosine Kinase Inhibitors in Advanced NSCLC: Brief Report of Clinical and Preclinical Proofs

Introduction: ALK tyrosine kinase inhibitors (TKIs) are the standard treatment for advanced ALK-positive NSCLC. Nevertheless, drug resistance inevitably occurs. Here, we report a case of a patient with metastatic ALK-positive lung adenocarcinoma with an impressive resistance to sequential treatment with ALK TKIs mediated by YES1 and MYC amplification in a contest of epithelial-to-mesenchymal transition and high progressive chromosomal instability... Conclusions: In conclusion, YES1 and MYC amplifications are candidates to justify a rapid acquired resistance to crizotinib entailing primary brigatinib and lorlatinib resistance. In this context, a combination strategy of ALK TKI with dasatinib could be effective to overcome a rapid resistance. READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2022.100278

Authors: Roberta Minari, Samuel Valentini, Denise Madeddu, Andrea Cavazzoni, Silvia La Monica, Costanza Anna Maria Lagrasta, Roberto Bertorelli, Veronica De Sanctis, Paola Fassan, Cinzia Azzoni, Lorena Bottarelli, Caterina Frati, Letizia Gnetti, Francesco Facchinetti, Pier Giorgio Petronini, Roberta Alfieri, Alessandro Romanel, Marcello Tiseo

Case StudyKirk SmithFebruary 1, 2022NSCLC, ALK TKIs, Resistance mechanism, YES1 amplification, MYC amplification

Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing

By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC. Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.01.1615

Authors: Yunpeng Yang, Jie Huang, Tao Wang, Jianya Zhou, Jing Zheng, Jifeng Feng, Wu Zhuang, Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Yunpeng Liu, Zhendong Zheng, Gaofeng Li, Huijie Wang, Shundong Cang, Ning Wu, Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Li Mao, Giovanni Selvaggi, Larry Zhu, Shanshan Xiao, Xiaobin Yuan, Zhilin Shen, Li Zhang

Pre-ClinicalKirk SmithMay 1, 2021ALK+, NSCLC, ctDNA, TP53, Resistance mechanism