Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing in ALK-Rearranged Non–Small-Cell Lung Cancer

Purpose: Patients with anaplastic lymphoma kinase (ALK)–rearranged non–small-cell lung cancer (NSCLC) inevitably develop resistance to ALK inhibitors. New diagnostic strategies are needed to assess resistance mechanisms and provide patients with the most effective therapy. We asked whether single circulating tumor cell (CTC) sequencing can inform on resistance mutations to ALK inhibitors and underlying tumor heterogeneity in ALK-rearranged NSCLC. Conclusions: Our results highlight the genetic heterogeneity and clinical utility of CTCs to identify therapeutic resistance mutations in ALK-rearranged patients. Single CTC sequencing may be a unique tool to assess heterogeneous resistance mechanisms and help clinicians for treatment personalization and resistance options to ALK-targeted therapies. READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-19-1176

Authors: Emma Pailler, Vincent Faugeroux, Marianne Oulhen, Laura Mezquita, Mélanie Laporte, Aurélie Honoré, Yann Lecluse, Pauline Queffelec, Maud NgoCamus, Claudio Nicotra, Jordi Remon, Ludovic Lacroix, David Planchard, Luc Friboulet, Benjamin Besse and Françoise Farace

$Squamous Cell Transformation of Primary Lung Adenocarcinoma in a Patient With EML4-ALK Fusion Variant 5 Refractory to ALK Inhibitors$

Squamous Cell Transformation of Primary Lung Adenocarcinoma in a Patient With EML4-ALK Fusion Variant 5 Refractory to ALK Inhibitors

Background: Originally discovered in lymphomas,1 the ALK fusion oncogene with gain-of-function cytoplasmic tyrosine kinase activity has since been identified as an oncogenic driver in 3% to 10% of patients with non–small cell lung cancer (NSCLC).2,3 FDA approval of crizotinib, a small molecule ALK tyrosine kinase inhibitor (TKI), only 3 years after the discovery of the ALK fusion oncogene represents one of the most rapid bench-to-bedside translational advances in the history of targeted cancer therapy.4 Among the many fusion partners that have been reported, EML4 is the most common gene partner of ALK through a paracentric inversion of chromosome 2 inv(2) (p21;p23). We previously reported that in a cohort of 200 NSCLC specimens, the EML4-ALK–positive transcripts included 109 variant 1 (V1; 54.5%), 20 V2 (10.0%), 68 V3 (34.0%), and 3 V5a (1.5%) variants.5 Most (n=188; 94.0%) EML4-ALK–positive NSCLC tumors had adenocarcinoma histology... Conclusions: To our knowledge, this is the first..... READ ARTICLE

Journal of National Comprehensive Cancer Network DOI:10.6004/jnccn.2019.7291

Authors: Jay Gong, Jeffrey P. Gregg, Weijie Ma, Ken Yoneda, Elizabeth H. Moore, Megan E. Daly, Yanhong Zhang, Melissa J. Williams, Tianhong Li

Variable Response to ALK Inhibitors in NSCLC with a Novel MYT1L-ALK Fusion

... We discuss the initial report of a myelin transcription factor 1 like gene (MYT1L)-ALK fusion identified in the tumor of a patient with metastatic NSCLC, and the tumor's unique response to treatment... In this case, NGS revealed a large duplication event in chromosome 2, resulting in a novel MYT1L-ALK fusion. Myelin transcription factor 1-like protein is located on the cytoplasmic surface of the Golgi membranes and the endoplasmic reticulum and is an important factor in the cell cycle (specifically, in checkpoint recovery).4 Because ALK fusion partners may be a determinant of response to treatment and its possible future resistance type,5 detection of these fusions is crucial. Fluorescence in situ hybridization testing for ALK failed to detect the fusion in either the primary lung cancer and the liver metastases. The ability of NGS to detect ALK fusions and their fusion partners may increase patients’ therapeutic options. Identifying novel events such as the MYT1L-ALK fusion may b..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.10.169

Authors: Terrence C. Tsou, Kyle Gowen, Siraj M. Ali, Vincent A.Miller, Alexa B. Schrock, Christine M. Lovly, Karen L. Reckamp

EditorialKirk SmithFebruary 1, 2019ALK Inhibitors, NSCLC, MYT1L-ALK Fusion

Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer

The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4–ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4–ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-..... READ ARTICLE

Cancer Discovery DOI:10.1158/2159-8290.CD-17-1256

Authors: Yoda S, Lin JJ, Lawrence MS, Burke BJ, Friboulet L, Langenbucher A, Dardaei L, Prutisto-Chang K, Dagogo-Jack I, Timofeevski S, Hubbeling H, Gainor JF, Ferris LA, Riley AK, Kattermann KE, Timonina D, Heist RS, Iafrate AJ, Benes CH, Lennerz JK, Mino-Kenudson M, Engelman JA, Johnson TW, Hata AN, Shaw AT.

Pre-ClinicalKirk SmithApril 12, 2018ALK Inhibitors, Lorlatinib, Resistance, ALK Mutations