Tobacco smoking and cessation and PD-L1 inhibitors in non-small cell lung cancer (NSCLC): a review of the literature

Background: Programmed death ligand 1 (PD-L1) targeting immunotherapies, as pembrolizumab and nivolumab, have significantly improved outcome in patients with non-small cell lung cancer (NSCLC). Tobacco smoking is the number one risk factor for lung cancer and is linked to 80%–90% of these cancers. Smoking during cancer therapy may influence on radiotherapy and chemotherapy outcome. We aimed to review the knowledge in immunotherapy... Conclusions: Tobacco smoking patients with NSCLC generally have a higher PD-L1 tumour proportion score and experience a better ORR of immunotherapy than no smokers. There is little evidence on the effect of smoking during immunotherapy, but one study (KEYNOTE-024) may indicate survival gains of smoking cessation. READ ARTICLE

ESMO Open DOI:10.1136/esmoopen-2018-000406

Authors: Jan Norum, Carsten Nieder

Review PaperKirk SmithJuly 1, 2018Lung cancer, PD-L1, immunotherapy, tobacco, smoking, cessation

ADAURA: Phase III, Double-blind, Randomized Study of Osimertinib Versus Placebo in EGFR Mutation-positive Early-stage NSCLC After Complete Surgical Resection

Currently, the role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as adjuvant therapy for early-stage non–small-cell lung cancer after complete surgical tumor resection remains under investigation. We present the rationale and study design for the ADAURA (ClinicalTrials.gov identifier, NCT02511106) trial, a multicenter, double-blind, randomized, placebo-controlled study. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2018.04.004

Authors: Yi-LongWu, Roy S. Herbst, Helen Mann, Yuri Rukazenkov, Marcelo Marotti and MasahiroTsuboi

Overcoming drug-tolerant cancer cell subpopulations showing AXL activation and epithelial–mesenchymal transition is critical in conquering ALK-positive lung cancer

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non–small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)-resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI resistance and EMT changes in both ALK-TKI-resistant and TGF-β1-exposed H..... READ ARTICLE

Oncotarget DOI:10.18632/oncotarget.25531

Authors: Shinji Nakamichi, Masahiro Seike, Akihiko Miyanaga, Mika Chiba, Fenfei Zou, Akiko Takahashi, Arimi Ishikawa, Shinobu Kunugi, Rintaro Noro, Kaoru Kubota, and Akihiko Gemma

Pre-ClinicalKirk SmithJune 5, 2018ALK, lung cancer, resistance, EMT, AXL

Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK)

Highlights • We discovered novel ALK PROTACs (MS4077 and MS4078) and their close analogs as negative controls. • MS4077 and MS4078 potently reduced cellular ALK protein levels in a cereblon and proteasome dependent manner. • MS4077 and MS4078 potently inhibited cellular ALK signaling. • MS4077 and MS4078 effectively inhibited cancer cell proliferation. • MS4078 displayed good plasma exposure in mice, thus is suitable for in vivo efficacy studies. READ ARTICLE

European Journal of Medicinal Chemistry DOI: 10.1016/j.ejmech.2018.03.071

Authors: Chengwei Zhang, Xiao-RanHan, Xiaobao Yang, Biao Jiang, Jing Liu, Yue Xiong, Jian Jin

Pre-ClinicalKirk SmithMay 10, 2018PROTAC, Protein degrader, ALK, Lymphoma, Lung cancer

Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in ALK and EGFR Driven Non–Small Cell Lung Cancer

Radiosurgery for multiple BMs is controversial, yet patients with EGFR-mutated and ALK-rearranged NSCLC may be uniquely suited to benefit from this approach. These results support single and multiple courses of radiosurgery without WBRT for patients with oncogene-addicted NSCLC with four or more BMs. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2017.12.006

Authors: Tyler P. Robin, Ross Camidge, Kelly Stuhr, Sameer K. Nath, Robert E. Breeze, Jose M. Pacheco, Arthur K. Liu, Laurie E. Gaspar, Thomas Purcell, Robert C. Doebele, Brian D. Kavanagh and Chad G. Rusthoven

Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer

Advanced anaplastic lymphoma kinase (ALK) fusion-positive non–small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2017.76.2294

Authors: Lin JJ, Zhu VW, Yoda S, Yeap BY, Schrock AB, Dagogo-Jack I, Jessop NA, Jiang GY, Le LP, Gowen K, Stephens PJ, Ross JS, Ali SM, Miller VA, Johnson ML, Lovly CM, Hata AN, Gainor JF, Iafrate AJ, Shaw AT, Ou SI

Real-World OutcomesKirk SmithApril 20, 2018EML4-ALK, Variant, Resistance

Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1). READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.7b01655

Authors: Chelsea E. Powell, Yang Gao, Li Tan, Katherine A. Donovan, Radosław P. Nowak, Amanda Loehr, Magda Bahcall, Eric S. Fischer, Pasi A. Jänne, Rani E. George, and Nathanael S. Gray

Precision medicine against ALK-positive non-small cell lung cancer: beyond crizotinib

Patients with oligometastatic (OM) non-small cell lung cancer (NSCLC) have favorable outcomes compared to patients presenting with diffuse metastatic disease. Recent randomized trials have demonstrated safety and efficacy signals for local ablative therapies with radiotherapy, surgery, or radiofrequency ablation for OM-NSCLC patients alongside systemic therapies. However, it remains unclear whether local ablative therapy (LAT) should be offered either upfront preceding systemic therapies or following initial systemic therapies as local consolidative therapy (LCT). Establishing optimal timing of RT and systemic therapy combinations is essential to maximize efficacy while maintaining safety. Most published randomized trial evidence surrounding the benefits of LAT and systemic therapies were generated from OM-NSCLC patients receiving cytotoxic chemotherapy agents. With increasing use of novel agents such as targeted therapies (i.e., tyrosine kinase inhibitors) and immune checkpoint inhibitors in management of metastatic NSCLC patients, LAT timing may need to be modulated based on the use of specific agents. This narrative review will discuss the current evidence on either upfront LAT or LCT for OM-NSCLC based on published trials and cohort studies. We briefly explored the possible biological mechanisms of the potential clinical advantages of either approach. This review also summarized the ongoing trials incorporating both upfront LAT and LCT, and considerations for future LAT strategies. READ ARTICLE

Medical Oncology DOI:10.1007/s12032-018-1133-4

Authors: Biagio Ricciuti, Andrea De Giglio, Carmen Mecca, Cataldo Arcuri, Sabrina Marini, Giulio Metro, Sara Baglivo, Angelo Sidoni, Guido Bellezza, Lucio Crinò and Rita Chiari

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

Treating ALK-positive non-small cell lung cancer

Targeting genomic alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, have radically changed the treatment of patients with non-small cell lung cancer (NSCLC). In the case of ALK-rearranged gene, subsequent rapid development of effective genotype-directed therapies with ALK tyrosine kinase inhibitors (TKIs) triggered major advances in the personalized molecularly based approach of NSCLC. Crizotinib was the first-in-class ALK TKI with proven superiority over standard platinum-based chemotherapy for the 1st-line therapy of ALK-rearranged NSCLC patients. However, the acquired resistance to crizotinib and its diminished efficacy to the central nervous system (CNS) relapse led to the development of several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib. To date, four ALK TKIs, crizotinib, ceritinib, alectinib and brigatinib have received approval from the Food and Drug Admin..... READ ARTICLE

Annals of Translational Medicine DOI:10.21037/atm.2017.11.34

Authors: Dimitrios C. Ziogas,corresponding author Anna Tsiara, Georgios Tsironis, Maria Lykka, Michalis Liontos, Aristotelis Bamias, and Meletios-Athanasios Dimopoulos

Diagnostic accuracy of PCR for detecting ALK gene rearrangement in NSCLC patients: A systematic review and meta-analysis

NGS evaluation with the Oncomine Solid Tumour Fusion transcript kit and RT-PCR proved to have high sensitivity and specificity, advocating their use in routine practice. For maximal sensitivity and specificity, ALK status should be assessed by using two techniques and a third one in discordant cases. We therefore propose a customizable testing algorithm. These findings significantly influence existing testing paradigms and have clear clinical and economic impact. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2017.11.117

Authors: Igor Letovanec, Stephen Finn, Panagiota Zygoura, Paul Smyth, Alex Soltermann, Lukas Bubendorf, Ernst-Jan Speel, Antonio Marchetti, Daisuke Nonaka, Kim Monkhorst, Henrik Hager, Miguel Martorell, Aleksandra Sejda, Richard Cheney, Javier Hernandez-Losa, Eric Verbeken, Walter Weder, Spasenija Savic, Alessia Di Lorito, Atilio Navarro, Enriqueta Felip, Arne Warth, Paul Baas, Peter Meldgaard, Fiona Blackhall, Anne-Marie Dingemans, Hendrik Dienemann, Rafal Dziadziuszko, Johan Vansteenkiste, Cathal O'Brien, Thomas Geiger, Jon Sherlock, Jeoffrey Schageman, Urania Dafni, Roswitha Kammler, Keith Kerr, Erik Thunnissen, Rolf Stahel, Solange Peters, Rolf A. Stahel, Rafael Rosell, Fiona Blackhall, Urania Dafni, Keith M. Kerr, Miguel Ángel Molina, Lukas Bubendorf, Walter Weder, Erik Thunnissen, Solange Peters, Stephen Finn, Anita Hiltbrunner, Roswitha Kammler, Thomas Geiger, Nesa Marti, Urania Dafni, Zoi Tsourti, Varvara Polydoropoulou, Panagiota Zygoura, Stephen Finn, Paul Smyth, Cathal O’Brien, Steven Gray, Walter Weder, Alex Soltermann, Isabelle Opitz, Alessandra Curioni, Lukas Bubendorf, Spasenija Savic, Didier Lardinois, Anne-Marie Dingemans, Ernst-Jan M. Speel, Andrea Ruland, Antonio Marchetti, Alessia Di Lorito, Graziano De Luca, Sara Malatesta, Fiona Blackhall, Daisuke Nonaka, Anne Marie Quinn, Lynsey Franklin, Wojciech Biernat, Ania Wrona, Witold Rzyman, Jacek Jassem, Peter Meldgaard, Henrik Hager, Line B. Madsen, Carlos Camps, Miguel Martorell, Eloisa Jantus-Lewintre, Ricardo Guijarro, Keith M. Kerr, Marianne Nicolson, David A.J. Stevenson, William Mathieson, Paul Baas, Jeroen de Jong, Kim Monkhorst, Erik Thunnissen, Egbert Smit, Coralien van Setten, Joop de Langen, Enriqueta Felip, Javier Hernandez-Losa, Irene Sansano, Richard Cheney, Mary Beth Pine, Mary Reid, Elizabeth Taylor, Kristiaan Nackaerts, Christophe Dooms, Els Wauters, Sara Van Der Borght, Hendrik Dienemann, Thomas Muley, Arne Warth

SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib—a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK—and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. Treatment with SHP099, the recently discovered small-molecule inhibitor of SHP2, in combination with the ALK tyrosine kinase inhibitor (TKI) ceritinib halted the growth of resistant PDCs through preventing compensatory RAS and ERK1 and ERK2 (ERK1/2) reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent mechanisms underlying resistance. READ ARTICLE

Nature Medicine DOI: 10.1038/nm.4497

Authors: Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Katherine X Shaw, Satoshi Yoda, Grainne Kerr, Kristine Yu, Jinsheng Liang, Yichen Cao, Yan Chen, Michael S Lawrence, Adam Langenbucher, Justin F Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David T Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard H DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice T Shaw, Aaron N Hata, Cyril H Benes, Fang Li, Jeffrey A Engelman

Pre-ClinicalKirk SmithMarch 1, 2018SHP2, ALK, TKI

Cell death-based treatment of lung adenocarcinoma

The most common type of lung cancer is adenocarcinoma (ADC), comprising around 40% of all lung cancer cases. In spite of achievements in understanding the pathogenesis of this disease and the development of new approaches in its treatment, unfortunately, lung ADC is still one of the most aggressive and rapidly fatal tumor types with overall survival less than 5 years. Lung ADC is often diagnosed at advanced stages involving disseminated metastatic tumors. This is particularly important for the successful development of new approaches in cancer therapy. The high resistance of lung ADC to conventional radiotherapies and chemotherapies represents a major challenge for treatment effectiveness. Here we discuss recent advances in understanding the molecular pathways driving tumor progression and related targeted therapies in lung ADCs. In addition, the cell death mechanisms induced by different treatment strategies and their contribution to therapy resistance are analyzed. The focus is on ap..... READ ARTICLE

Cell Death & Disease DOI:10.1038/s41419-017-0063-y

Authors: Tatiana V. Denisenko, Inna N. Budkevich and Boris Zhivotovsky

Review PaperKirk SmithFebruary 18, 2018lung cancer

Concise Review: Resistance to Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: The Role of Cancer Stem Cells

Among the potential mechanisms involved in resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer, the manifestation of stem-like properties in cancer cells seems to have a crucial role. Alterations involved in the development of TKI resistance may be acquired in a very early phase of tumorigenesis, supporting the hypothesis that these aberrations may be present in cancer stem cells (CSCs). In this regard, the characterization of tumor subclones in the initial phase and the identification of the CSCs may be helpful in planning a specific treatment to target selected biomarkers, suppress tumor growth, and prevent drug resistance. The aim of this review is to elucidate the role of CSCs in the development of resistance to TKIs and its implication for the management of patients. READ ARTICLE

Stem Cells DOI:10.1002/stem.2787

Authors: Marzia Del Re, Elena Arrigoni, Giuliana Restante, Antonio Passaro, Eleonora Rofi, Stefania Crucitta, Filippo De Marinis, Antonello Di Paolo, Romano Danesi

ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

ALK positive non-small cell lung cancer is highly responsive to ALK inhibitors such as crizotinib, but drug resistance typically develops within a year of treatment. In this study we investigated whether IGF-1R is an independent druggable target in ALK-positive lung cancer cells. We confirmed that combination ALK and IGF-1R inhibitor treatment is synergistically cytotoxic to ALK-positive lung cancer cells and that this remains the case for at least 12 days after initial exposure to crizotinib. ALK-positive cells with acquired resistance to crizotinib did not acquire cross-resistance to IGF-1R inhibition, though combination treatment in the resistant cells gave additive rather than synergistic cytotoxicity. We concluded that IGF-1R is an independent druggable target in ALK-positive lung cancer and support the trial of combination treatment. READ ARTICLE

Scientific Reports DOI:10.1038/s41598-017-14289-w

Authors: Christabel Wilson, Mhairi Nimick, Hayley Nehoff, John C. Ashton

Pre-ClinicalKirk SmithOctober 24, 2017ALK, IGF-1R, Crizotinib

Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer

During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee–assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib).
As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC READ ARTICLE

the New England Journal of Medicine DOI:10.1056/NEJMoa1704795

Authors: Solange Peters, M.D., Ph.D., D. Ross Camidge, M.D., Ph.D., Alice T. Shaw, M.D., Ph.D., Shirish Gadgeel, M.D., Jin S. Ahn, M.D., Dong-Wan Kim, M.D., Ph.D., Sai-Hong I. Ou, M.D., Ph.D., Maurice Pérol, M.D., Rafal Dziadziuszko, M.D., Rafael Rosell, M.D., Ph.D., Ali Zeaiter, M.D., Emmanuel Mitry, M.D., Ph.D., Sophie Golding, M.Sc., Bogdana Balas, M.D., Johannes Noe, Ph.D., Peter N. Morcos, Pharm.D., and Tony Mok, M.D.

Clinical TrialsKirk SmithAugust 31, 2017Alectinib, Crizotinib, ALEX

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3

These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. READ ARTICLE

Lancet DOI: 10.1016/S0140-6736(17)30565-2

Authors: Toyoaki Hida MD, Hiroshi Nokihara MD, Masashi Kondo MD, Young Hak Kim MD, Koichi Azuma MD, Takashi Seto MD, Yuichi Takiguchi MD, Makoto Nishio MD, Hiroshige Yoshioka MD, Fumio Imamura MD, Katsuyuki Hotta MD, Satoshi Watanabe MD, Koichi Goto MD, Miyako Satouchi MD, Toshiyuki Kozuki MD, Takehito Shukuya MD, Kazuhiko Nakagawa MD, Tetsuya Mitsudomi MD, Nobuyuki Yamamoto MD,Takashi Asakawa PhD, Ryoichi Asabe MS, Tomohiro Tanaka MS, Tomohide Tamura MD

Clinical TrialsKirk SmithJuly 1, 2017ALEX Study, alectinib, crizotinib

A Sensitive ALK Immunohistochemistry Companion Diagnostic Test Identifies Patients Eligible for Treatment with Crizotinib

Introduction: The availability of high-quality, rigorously validated diagnostic tests that can be broadly implemented is necessary to efficiently identify patients with anaplastic lymphoma kinase (ALK)-positive NSCLC who can potentially benefit from treatment with crizotinib. Here we present data on the recently approved Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Tucson, AZ), the only immunohistochemistry (IHC)-based assay linked to treatment outcome... Conclusions: The ALK (D5F3) CDx assay is a stand-alone companion diagnostic test for identification of patients for treatment with crizotinib. This automated assay provides an effective option to accurately and rapidly identify patients with ALK-positive NSCLC. The simple binary scoring algorithm results in high reader-to-reader precision. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2017.01.020

Authors: Trish Thorne-Nuzzo, Crystal Williams, Alice Catallini, June Clements, Shalini Singh, James Amberson, Kim Dickinson, Zoran Gatalica, Steffan N. Ho, Isabell Loftin, Abigail McElhinny, Penny Towne

A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer

A high rate of aerobic glycolysis is a hallmark of malignant transformation. Accumulating evidence suggests that diverse regulatory mechanisms mediate this cancer-associated metabolic change seen in a wide spectrum of cancer. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein is found in approximately 3–7% of non-small cell lung carcinomas (NSCLC). Molecular evidence and therapeutic effectiveness of FDA-approved ALK inhibitors indicated that EML4-ALK is a driving factor of lung tumorigenesis. A recent clinical study showed that NSCLC harboring EML4-ALK rearrangements displayed higher glucose metabolism compared with EML4-ALK-negative NSCLC. In the current work, we presented evidence that EML4-ALK is coupled to overexpression of hexokinase II (HK2), one of the rate-limiting enzymes of the glycolytic pathway. The link from EML4-ALK to HK2 upregulation is essential for a high rate of glycolysis and proliferation of EML4-ALK-rearranged..... READ ARTICLE

Oncogene DOI: 10.1038/onc.2016.150

Authors: Y Ma, C Yu, E M Mohamed, H Shao, L Wang, G Sundaresan, J Zweit, M Idowu & X Fang

Pre-ClinicalKirk SmithNovember 1, 2016PI3K/AKT, ALK

The role of the ALK receptor in cancer biology

This review summarises the latest research on the receptor tyrosine kinase ALK, and how this information can guide the management of patients with cancer that is ALK-positive. A variety of ALK gene alterations have been described across a range of tumour types, including point mutations, deletions and rearrangements. A wide variety of ALK fusions, in which the kinase domain of ALK and the amino-terminal portion of various protein partners are fused, occur in cancer, with echinoderm microtubule-associated protein-like 4 (EML4)-ALK being the most prevalent in non-small-cell lung cancer (NSCLC). Different ALK fusion proteins can mediate different signalling outputs, depending on properties such as subcellular localisation and protein stability. The ALK fusions found in tumours lack spatial and temporal regulation, which can also affect dimerisation and substrate specificity. Two ALK tyrosine kinase inhibitors (TKIs), crizotinib and ceritinib, are currently approved in Europe for use in ALK-positive NSCLC and several others are in development. These ALK TKIs bind slightly differently within the ATP-binding pocket of the ALK kinase domain and are associated with the emergence of different resistance mutation patterns during therapy. This emphasises the need to tailor the sequence of ALK TKIs according to the ALK signature of each patient. Understanding the role of ALK in tumour biology is key to further optimising therapeutic strategies for ALK-positive disease. READ ARTICLE

Annals of Oncology DOI: 10.1093/annonc/mdw301

Authors: B. Hallberg, R.H. Palmer

Review PaperKirk SmithSeptember 1, 2016EML4-ALK, NSCLC, TKI, cancer biology, anaplastic lymphoma kinase (ALK)