Concomitance of a novel RMDN2-ALK fusion and an EML4-ALK fusion in a lung adenocarcinoma

Here, we present a lung adenocarcinoma with two ALK fusions, a novel RMDN2-ALK fusion accompanied by an EML4-ALK fusion, detected by a targeted next generation sequencing assay. The genomic translocation breakpoints of the RMDN2-ALK fusion were mapped to intron 2 for RMDN2 and exon 15 for ALK, and EML4-ALK breakpoints were mapped to intron 13 for EML4 and intron 19 for ALK. ALK break-apart FISH detected multiple ALK rearrangements, a gene fusion panel (NanoString) test confirmed the EML4-ALK fusion, and RNA-sequencing revealed two ALK fusions. The RMDN2 gene locates at the short arm of chromosome 2 between ALK and EML4 genes. The intact ALK kinase domain fused to RMDN2. Genome-wide copy number variants were found in multiple chromosome arms and the short arm of chromosome 2, suggestive of complex rearrangements. Further detailed analyses of breakpoints and copy number variants may shed light on mechanisms of their formation and pathogenesis in lung malignancies. READ ARTICLE

Cancer Genetics DOI: 10.1016/j.cancergen.2021.06.004

Authors: Liqun Jiang, Suping Chen, Victoria Stinnett, Lisa Haley, Laura Morsberger, Alison Shane, Melanie Hardy, Kirstin Smith, Christopher D. Gocke, Ming-Tseh Lin and Ying S. Zou,

Immunotherapy and Vaccination in Surgically Resectable Non-Small Cell Lung Cancer (NSCLC)

Early-stage NSCLC (stages I and II, and some IIIA diseases) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases, with surgery being its main treatment modality. The risk of disease recurrence and cancer-related death, however, remains high among NSCLC patients after complete surgical resection. In previous studies on the long-term follow-up of post-operative NSCLC, the results showed that the five-year survival rate was about 65% for stage IB and about 35% for stage IIIA diseases. Platinum-based chemotherapy with or without radiation therapy has been used as a neoadjuvant therapy or post-operative adjuvant therapy in NSCLC, but the improvement of survival is limited. Immune checkpoint inhibitors (ICIs) have effectively improved the 5-year survival of advanced NSCLC patients. Cancer vaccination has also been explored and used in the prevention of cancer or reducing disease recurrence in resected NSCLC. Here, we review studies that have focused on the use of immunotherapies (i.e., ICIs and vaccination) in surgically resectable NSCLC. We present the results of completed clinical trials that have used ICIs as neoadjuvant therapies in pre-operative NSCLC. Ongoing clinical trials investigating ICIs as neoadjuvant and adjuvant therapies are also summarized. READ ARTICLE

Vaccines DOI: 10.3390/vaccines9070689

Authors: Chiu L.-C., Lin S.-M., Lo Y.-L., Kuo S.C.-H., Yang C.-T. and Hsu P.-C.

IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma

Genome-wide CRISPR activation and knockout screens identify genes involved in modulating sensitivity to crizotinib in NPM1-ALK+ ALCL.

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor–relapsed patient tumors, we show that resistance to ALK inhibitio..... READ ARTICLE

Blood DOI:10.1182/blood.2019003793

Authors: Nina Prokoph, Nicola A. Probst, Liam C. Lee, Jack M. Monahan, Jamie D. Matthews, Huan-Chang Liang, Klaas Bahnsen, Ivonne A. Montes-Mojarro, Elif Karaca-Atabay, Geeta G. Sharma, Vikas Malik, Hugo Larose, Sorcha D. Forde, Stephen P. Ducray, Cosimo Lobello, Qi Wang, Shi-Lu Luan, Šárka Pospíšilová, Carlo Gambacorti-Passerini, G. A. Amos Burke, Shahid Pervez, Andishe Attarbaschi, Andrea Janíková, Hélène Pacquement, Judith Landman-Parker, Anne Lambilliotte, Gudrun Schleiermacher, Wolfram Klapper, Ralf Jauch, Wilhelm Woessmann, Gilles Vassal, Lukas Kenner, Olaf Merkel, Luca Mologni, Roberto Chiarle, Laurence Brugières, Birgit Geoerger, Isaia Barbieri and Suzanne D. Turner

Pre-Clinical, group5Kirk SmithJune 23, 2021ALCL, NPM1-ALK, IL10RA, Stat3

SHP2 inhibition enhances the effects of tyrosine kinase inhibitors in preclinical models of treatment-naïve ALK-, ROS1-, or EGFR-altered non-small-cell lung cancer

After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) as well as c-ros oncogene 1 (ROS1). The mechanisms underlying this type of resistance are unknown. Here we report the potential role of Src homology 2 domain-containing phosphatase 2 (SHP2) in the residual cells of ALK/ROS1/EGFR-altered non-small-cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both in vitro and in vivo. Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC. READ ARTICLE

Molecular Cancer Therapeutics DOI: 10.1158/1535-7163.MCT-20-0965

Authors: Hirohisa Kano, Eiki Ichihara, Hiromi Watanabe, Kazuya Nishii, Chihiro Ando, Takamasa Nakasuka, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda and Katsuyuki Kiura

Pre-Clinical, group5Kirk SmithJune 22, 2021ALK, ROS1, EGFR, SHP2, NSCLC, ERK

David Marshak and Katy Wong from Foundation Medicine, a private company who does ngs testing and liquid biopsy

David Marshak and Katy Wong educate the ALK Positive Community about Biomarker testing. SEE VIDEO

ALK Positive Inc.

Authors: David Marshak and Katy Wong

Video, group5Kirk SmithJune 20, 2021ALKtALK

ALK Research Special: Let’s talk about the basics of ALK Genetics

Alice Chou takes you back to high school and becomes your science teacher going over a special biology lesson on ALK Genetics. READ ARTICLE

Pre-Clinical, group5Kirk SmithJune 20, 2021ALK, Genetics, Alice Chou, ALK Research Special

New Insights into the Clinical Implications of Yes-Associated Protein in Lung Cancer: Roles in Drug Resistance, Tumor Immunity, Autophagy, and Organoid Development

Innovative advancements in lung cancer treatment have developed over the past decade with the advent of targeted and immune therapies. Yes-associated protein (YAP), an effector of the Hippo pathway, promotes the resistance of these targeted drugs and modulates tumor immunity in lung cancer. YAP is involved in autophagy in lung cancer and plays a prominent role in forming the tubular structure in lung organoids and alveolar differentiation. In this review, we discuss the central roles of YAP in lung cancer and present YAP as a novel target for treating resistance to targeted therapies and immunotherapies in lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13123069

Authors: Yoo G, Park D, Kim Y and Chung C.

Review Paper, group5Kirk SmithJune 17, 2021YAP, TAZ, Hippo pathway, lung cancer, drug resistance, EGFR-TKI, PD-L1, autophagy, organoid

Radiotherapy for Oligometastatic Non–Small Cell Lung Cancer: Past, Present, and Future

Historically, patients with stage IV non–small cell lung cancer (NSCLC) have been treated with chemotherapy alone, reserving local therapies for symptom palliation. However, evidence has accumulated that a subset of patients with oligometastatic NSCLC (OM-NSCLC) may benefit from local ablative therapies (LATs). In this article, we review the data that have formed the rationale for LAT, specifically radiotherapy, and the prospective trials that support its use in this population. Finally, we examine the evolving role of LAT in patients with OM-NSCLC in the context of immunotherapy and targeted therapies, as well as discuss ongoing clinical trials incorporating LAT in these patients. READ ARTICLE

ONCOLOGY DOI: 10.46883/onc.2021.3506.0311

Authors: Neal S. McCall and Kristin A. Higgins

Genomic and experimental evidence that alternate transcription initiation of the Anaplastic Lymphoma Kinase (ALK) kinase domain does not predict single agent sensitivity to ALK inhibitors

Genomic data can facilitate personalized treatment decisions by enabling therapeutic hypotheses in individual patients. Conditional selection, which includes mutual exclusivity, is a signal that has been empirically useful for identifying mutations that may be sensitive to single agent targeted therapies. However, a low mutation frequency can underpower this signal for rare variants and prevent robust conclusions from genomic data. We develop a resampling based method for the direct pairwise comparison of conditional selection between sets of gene pairs. This effectively creates positive control guideposts of mutual exclusivity in known driver genes that normalizes differences in mutation abundance. We applied this method to a transcript variant of anaplastic lymphoma kinase (ALK) in melanoma, termed ALKATI, which has been the subject of a recent controversy in the literature. We reproduced some of the original cell transformation experiments, performed rescue experiments, and analyzed..... READ ARTICLE

BioRxiv DOI:10.1101/696294

Authors: Haider Inam, Ivan Sokirniy, Yiyun Rao, Anushka Shah, Farnaz Naeemikia, Edward O’Brien, Cheng Dong, David McCandlish, Justin R Pritchard

Comparison of lorlatinib, alectinib and brigatinib in ALK inhibitor–naive/untreated ALK-positive advanced non-small-cell lung cancer: a systematic review and network meta-analysis

Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor–naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced non-small-cell lung cancer (NSCLC), the optimal option for these patients still remains undefined. We searched published reports that described the activity and safety of those novel ALK inhibitors (lorlatinib, alectinib and brigatinib) for ALK inhibitor–naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. Five randomized controlled trials were identified, covering 1111 subjects. In the network meta-analysis, lorlatinib seemed to prolong progression free survival than brigatinib (Hazard Ratio: 0.57, P = 0.03) and alectinib (Hazard ratio: 0.65, P = 0.05) for previously untreated patients with ALK-positive advanced NSCLC as assessed by the independent review committee. Meanwhile, lorlatinib significantly improved significant progression free sur..... READ ARTICLE

Journal of Chemotherapy DOI:10.1080/1120009X.2021.1937782

Authors: Lida Wang, Zhixin Sheng, Junying Zhang, Jiwu Song, Lili Teng, Liping Liu, Qianpeng Li, Baohong Wang, Bin Li

Review Paper, group5Kirk SmithJune 17, 2021Lorlatinib, alectinib, brigatinib, crizotinib, advanced NSCLC, meta-analysis

Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects

Immunogenic cell death (ICD) is clinically relevant because cytotoxicants that kill malignant cells via ICD elicit anticancer immune responses that prolong the effects of chemotherapies beyond treatment discontinuation. ICD is characterized by a series of stereotyped changes that increase the immunogenicity of dying cells: exposure of calreticulin on the cell surface, release of ATP and high mobility group box 1 protein, as well as a type I interferon response. Here, we examined the possibility that inhibition of an oncogenic kinase, anaplastic lymphoma kinase (ALK), might trigger ICD in anaplastic large cell lymphoma (ALCL) in which ALK is activated due to a chromosomal translocation. Multiple lines of evidence plead in favor of specific ICD-inducing effects of crizotinib and ceritinib in ALK-dependent ALCL: (i) they induce ICD stigmata at pharmacologically relevant, low concentrations; (ii) can be mimicked in their ICD-inducing effects by ALK knockdown; (iii) lose their effects in th..... READ ARTICLE

Cell, Death and Disease DOI:10.1038/s41419-021-03997-x

Authors: Adriana Petrazzuolo, Maria Perez-Lanzon, Isabelle Martins, Peng Liu, Oliver Kepp, Véronique Minard-Colin, Maria Chiara Maiuri & Guido Kroemer

Pre-Clinical, group5Kirk SmithJune 16, 2021ACLC, NPM1-ALK+, cell death, crizotinib, ceretinib

Lung Cancer Stem Cells—Origin, Diagnostic Techniques and Perspective for Therapies

Lung cancer is still a serious oncological problem worldwide. Thus, the biology of this cancer is of interest. Cancer stem cells (CSCs) are involved in tumor initiation and progression. Spontaneously occurring mutations accumulate in stem cells or/and progenitor cells throughout a person’s lifetime resulting in the formation of CSCs. In this review, we discuss the CSC hypothesis with an emphasis on age-associated changes that govern carcinogenesis. The evidence from the scientific literature, as well as our own results and observations, has been presented. READ ARTICLE

Cancers DOI: 10.3390/cancers13122996

Authors: Agata Raniszewska, Iwona Kwiecie, Elzbieta Rutkowska, Piotr Rzepecki and Joanna Domagała-Kulawik

Review Paper, group5Kirk SmithJune 15, 2021NSCLC, cancer stem cells, liquid biopsy, immunotherapy, aging, biopsy

Two novel strategies to overcome the resistance to ALK tyrosine kinase inhibitor drugs: Macrocyclic inhibitors and proteolysis-targeting chimeras

Lung cancer is the most malignant tumor in the worldwide. About 3%-5% non-small cell lung cancer (NSCLC) patients carry anaplastic lymphoma kinase (ALK) gene fusions and receive great benefits from ALK-targeted therapy. However, drug resistance inevitably occurs even with the most potent inhibitor drug lorlatinib. About half of the resistance are caused by alteration in ALK proteins for earlier ALK TKI drugs and near one-third of loratinib resistant cases are caused by compound mutations without current effective treatment strategy in clinic. Novel strategies are in great need to overcome drug resistance. Lately, two novel strategies have been developed and attracted great attentions for their potentials to overcome drug resistance problems: (1) developed small compact macrocyclic ALK kinase inhibitors and (2) developed ALK targeted proteolysis-targeting chimera (PROTAC) drugs. The macrocyclic molecules are small and compact in size, brain barrier permeable, and highly potent against lorlatinib-resistant compound mutations. Developed ALK targeted PROTAC molecules could degrade oncogenic ALK driver proteins. Some showed superiority in killing ALK positive cancer cells and inhibiting the growth of cells expressing G1202R resistant ALK proteins comparing to inhibitor drugs. The update on these two treatment strategies was reviewed. READ ARTICLE

MedComm DOI: 10.1002/mco2.42

Authors: Song X, Zhong H, Qu X, Yang L and Jiang B.

GRACE videos: 2020 TTF ALK SESSION RAEZ Sequence of ALK Inhibitors

In this video from the ALK + session from the event, Dr. Luis Raez discusses the sequence of ALK inhibitors. SEE VIDEO

GRACE - Global Resource for Advancing Cancer Education

Author: Luis Raez

Video, group5Kirk SmithJune 14, 2021sequence of ALK inhibitor

Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma

Methods: We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles. Results:While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC = − 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC = − 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine–cytokine receptor signaling, were differentially expressed be..... READ ARTICLE

Cancer Immunology, Immunotherapy DOI:doi.org/10.1007/s00262-021-02981-w

Authors: Jan Budczies, Martina Kirchner, Klaus Kluck, Daniel Kazdal, Julia Glade, Michael Allgäuer, Mark Kriegsmann, Claus-Peter Heußel, Felix J. Herth, Hauke Winter, Michael Meister, Thomas Muley, Torsten Goldmann, Stefan Fröhling, Martin Wermke, Cornelius F. Waller, Amanda Tufman, Martin Reck, Solange Peters, Peter Schirmacher, Michael Thomas, Petros Christopoulos, & Albrecht Stenzinger

Arsenic trioxide inhibits anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma through targeting ALK-fusion oncoprotein

Anaplastic lymphoma kinase (ALK) gene rearrangement and chimeric nucleophosmin (NPM)-ALK fusion oncoprotein were first identified in anaplastic large cell lymphoma (ALCL).1 Fusion of ALK to other genes have subsequently been found in other neoplasms, including clathrin heavy chain 1 (CLTC-ALK) in diffuse large B-cell lymphoma (DLBCL) and echinoderm microtubule associated protein like 4 (EML4-ALK) in non-small-cell lung carcinoma (NSCLC).2, 3 ALK-positive DLBCL is uncommon but aggressive, accounting for <1% of all DLBCLs, with <100 cases reported since its first description in 1997.4 ALK-positive DLBCL have an inferior clinical outcome when treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-derived regimens.5 CLTC-ALK is the most common genetic fusion in ALK-positive DLBCL, arising from t(2;17) and resulting in the chimeric oncoprotein CLTC-ALK with a constitutively activated ALK kinase domain.6 A selective ALK kinase inhibitor suppressed the growth of CLTC-ALK-positive DLBCL cells in vitro and in vivo, indicating CLTC-ALK to be a potential therapeutic target in ALK-positive DLBCL.7 Arsenic trioxide (As2O3) exerts anti-leukaemic activity by targeting the promyelocytic leukaemia/retinoic acid receptor alpha (PML-RARA) oncoprotein for degradation in acute promyelocytic leukaemia (APL). It also induces degradation of the mutant cytoplasmic NPM, NPMc+, in acute myeloid leukaemia (AML).8 We therefore proposed that As2O3 might also target NPM-ALK in ALCL. Previous work in our group has shown that As2O3 induces degradation of NPM-ALK fusion protein in ALK-positive ALCL in vitro and in vivo, thereby suppressing tumour growth of ALK-positive ALCL.9 Here we further hypothesised that As2O3 might also exhibit anti-lymphoma effect in ALK-positive DLBCL by targeting the CLTC-ALK fusion protein. READ ARTICLE

British Journal of Haematology DOI: 10.1111/bjh.17581

Authors: Yue L.-M., Chau D., Kwong Y.-L. and Tse E.

Bio-Nanocarriers for Lung Cancer Management: Befriending the Barriers

Lung cancer is a complex thoracic malignancy developing consequential to aberrations in a myriad of molecular and biomolecular signaling pathways. It is one of the most lethal forms of cancers accounting to almost 1.8 million new annual incidences, bearing overall mortality to incidence ratio of 0.87. The dismal prognostic scenario at advanced stages of the disease and metastatic/resistant tumor cell populations stresses the requisite of advanced translational interdisciplinary interventions such as bionanotechnology. This review article deliberates insights and apprehensions on the recent prologue of nanobioengineering and bionanotechnology as an approach for the clinical management of lung cancer. The role of nanobioengineered (bio-nano) tools like bio-nanocarriers and nanobiodevices in secondary prophylaxis, diagnosis, therapeutics, and theranostics for lung cancer management has been discussed. Bioengineered, bioinspired, and biomimetic bio-nanotools of considerate translational va..... READ ARTICLE

Nanomicro Letters DOI:10.1007/s40820-021-00630-6

Authors: Shruti Rawal and Mayur Patel

Brain Mets & CNS Coverage of MET signaling in NSCLC

Colorado University Updates on Lung Cancer Research: The Future for Lung Cancer & Targeted Therapies. SEE VIDEO

Author: University of colorado Cancer Center

Video, group5Kirk SmithJune 11, 2021Brain metastases, CNS, MET, NSCLC

Proximity Proteomics Has Potential for Extracellular Vesicle Identification

Extracellular vesicles (EVs) are biomarkers and mediators of intercellular communication. In biological samples, EVs are secreted by various types of cells. The proteomic identification of proteins expressed in EVs has potential to contribute to research and clinical applications, particularly for cancer. In this study, the proximity-labeling method-based proteomic approach was used for EV identification, labeling membrane components proximal to a given molecule on the EV membrane surface. Due to the small labeling range, proteins on the surface of the same EVs are likely to be labeled by selecting a given EV surface antigen. The protein group of cancer cell-secreted EV (cEV), which abundantly expresses a close homologue of L1 (CHL1), was examined using a model mouse for lung cancer (LC). cEV-expressed proteins were identified by proteomic analysis of enzyme-mediated activation of radical sources by comparing serum EVs from wild-type and LC mice. SLC4A1 was found to be co-expressed in CHL1-expressing EVs, highlighting EVs expressing both CHL1 and SLC4A1 as candidates for cEVs. Serum EVs expressing both CHL1 and caspase 14 were significantly elevated in LC patients compared with healthy individuals. Thus, the combination of proximity labeling and proteomic analysis allows for effective EV identification. READ ARTICLE

Journal of Proteome Research DOI: 10.1021/acs.jproteome.1c00149

Authors: Hisako Kaneda, Yui Ida, Ryusuke Kuwahara, Izumi Sato, Takanari Nakano, Haruhiko Tokuda, Tsuyoshi Sato, Takayuki Murakoshi, Koichi Honke and Norihiro Kotani

Diverse routes of Club cell evolution in lung adenocarcinoma

The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we address the cell-of-origin of LUAD, by employing lineage-tracing mouse models combined with a CRISPR/Cas9 system to induce an oncogenic Eml4-Alk rearrangement in virtually all epithelial cell types of the lung. We find that Club cells give rise to lung tumours with a higher frequency than AT2 cells. Based on whole genome methylome, we identified that tumours retain an ‘epigenetic memory’ derived from their originating cell type but also develop a tumour-specific pattern regardless of their origin. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, providing a link between lung regeneration and cancer initiation. On both routes, tumours lose their Club cell identity and gain an AT2-li..... READ ARTICLE

BioRxIV DOI:10.1101/2021.06.10.447936

Authors: Yuanyuan Chen, Reka Toth, Sara Chocarro, Dieter Weichenhan, Joschka Hey, Pavlo Lutsik, Stefan Sawall, Georgios T. Stathopoulos, Christoph Plass, Rocio Sotillo