Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non–small-cell lung cancer: a multicenter study using targeted next-generation sequencing

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non–small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients’ clinicopathologic characteristics and treatment outcomes were analyzed. Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers. READ ARTICLE

European Journal of Cancer DOI:10.1016/j.ejca.2021.06.043

Authors: Yen-Ting Lin, Chi-Lu Chiang, Jen-Yu Hung, Mei-Hsuan Lee, Wu-Chou Su, Shang-Yin Wu, Yu-Feng Wei, Kang-Yun Lee, Yen-Han Tseng, Jian Su, Hsin-Pei Chung, Chih-Bin Lin, Wen-Hui Ku, Tsai-Shin Chiang, Chao-Hua Chiu, Jin-Yuan Shih

SPACEWALK: A Remote Participation Study of ALK Resistance Leveraging Plasma Cell-Free DNA Genotyping

Through the leveraging of remote participation, plasma NGS offers an optimal mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations, though sensitivity depends on adequate tumor DNA samples. Repeat cfDNA analysis on therapy may offer an objective monitoring approach to remotely study treatment response. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtocrr.2021.100151

Authors: Marissa N. Lawrence, Rubii M. Tamen, Pablo Martinez, Alicia Sable-Hunt, Tony Addario, Pete Barbour, Tristan Shaffer, Seyed Ali Hosseini, Caterina Bertucci, Lee P. Lim, Fangxin Hong, Kesi Michael, George R. Simon, Jonathan W. Riess, Mark M. Awad, Geoffrey R. Oxnard

Real-World OutcomesKirk SmithFebruary 1, 2021ALK, Drug resistance, Plasma NGS, Remote participation

BRAF V600E mutation and MET amplification as resistance pathways of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in lung cancer

Background: Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. However, patients inevitably develop resistance to such therapies. To investigate novel mechanisms of resistance to second generation ALK inhibitors, we characterized and modeled ALK inhibitor resistance of ALK-positive patient-derived xenograft (PDX) models established from advanced-stage lung adenocarcinoma patients who have progressed on one or more ALK inhibitors. Conclusions: Bypass signaling pathway through c-MET and BRAF are independent mechanisms of resistance to alectinib. Individualized intervention against these resistance pathways could be viable therapeutic options in alectinib-refractory lung adenocarcinoma. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.05.018

Authors: Ruoshi Shi, Sebastiao N. Martins Filho, Ming Li, Aline Fares, Jessica Weiss, Nhu-An Pham, Olga Ludkovski, Vibha Raghavan, Quan Li, Deepti Ravi, Michael Cabanero, Nadeem Moghal, Natasha B. Leighl, Penelope Bradbury, Adrian Sacher, Frances A. Shepherd, Kazuhiro Yasufuku, Ming-Sound Tsao, Geoffrey Liu

ZX-29, a novel ALK inhibitor, induces apoptosis via ER stress in ALK rearrangement NSCLC cells and overcomes cell resistance caused by an ALK mutation

Although anaplastic lymphoma kinase (ALK) inhibitors have good clinical efficacy, the inevitable development of drug resistance is the most common obstacle to their clinical application. There is an urgent need to develop more effective and selective ALK inhibitors to overcome the problem of drug resistance. Here, we screened a series of ALK inhibitors and found that ZX-29 displayed potent cytotoxic activity against ALK rearrangement non-small cell lung cancer (NSCLC) NCI-H2228 cells. Then, we investigated the antitumor effects of ZX-29. We demonstrated that ZX-29 time- and dose-dependently inhibited the viability of NCI-H2228 cells, induced cell cycle arrest in the G1 phase, and then they subsequently progressed into cell death. The type of cell death induced by ZX-29 was apoptosis through endoplasmic reticulum (ER) stress. Interestingly, ZX-29 induced protective autophagy, and inhibiting autophagy could enhance the antitumor effect of ZX-29. Furthermore, ZX-29 suppressed tumor growth..... READ ARTICLE

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research DOI:10.1016/j.bbamcr.2020.118712

Authors: Wenfeng Gou, Zengqiang Li, Xiaobo Xu, Jiwei Shen, Ming Guo, Xuejiao Zhou, Xiaoning Zhang, Yingliang Wu, Xin Zhai, Daiying Zuo

Pre-ClinicalKirk SmithJuly 1, 2020ALK, NSCLC, ER stress, Apoptosis, Drug resistance

Drug resistance to targeted therapeutic strategies in non-small cell lung cancer

Rapidly developing molecular biology techniques have been employed to identify cancer driver genes in specimens from patients with non-small cell lung cancer (NSCLC). Inhibitors and antibodies that specifically target driver gene-mediated signaling pathways to suppress tumor growth and progression are expected to extend the survival time and further improve the quality of life of patients. However, the health of patients with advanced and metastatic NSCLC presents significant challenges due to treatment resistance, mediated by cancer driver gene alteration, epigenetic alteration, and tumor heterogeneity. In this review, we discuss two different resistance mechanisms in NSCLC targeted therapies, namely changes in the targeted oncogenes (on-target resistance) and changes in other related signaling pathways (off-target resistance) in tumor cells. We highlight the conventional mechanisms of drug resistance elicited by the complex heterogeneous microenvironment of NSCLC during targeted ther..... READ ARTICLE

Pharmacology & Therapeutics DOI:10.1016/j.pharmthera.2019.107438

Authors: Wen-juan Liu, Yue Du, Ru Wen, Ming Yang, JianXu

Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, including Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib, have been approved by the U.S. Food and Drug Administration (FDA) against ALK-positive NSCLCs. Novel type-I1/2 and type-II ALK inhibitors with improved kinase selectivity and enhanced capability to combat drug resistance have also been reported. Moreover, the "proteolysis targeting chimera" (PROTAC) technique has been successfully applied in developing ALK degraders, which opened a new avenue for targeted ALK therapies. This review provides an overview of the physiological and biological functions of ALK, the discovery and development of drugs targeting ALK by focusing on their chemotypes, activity, selectivity, and resistance as well as potential therapeutic strategies to overcome drug resistance. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.9b00446

Authors: Kong X, Pan P, Sun H, Xia H, Wang X, Li Y, Hou T.

Pre-ClinicalKirk SmithAugust 16, 2019Drug resistance, Peptides and proteins, Genetics, Inhibitors