Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib

Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study. READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2021.113335

Authors: Chaowei Ren, Ning Sun, Ying Kong, Xiaojuan Qu, Haixia Liu, Hui Zhong, Xiaoling Song, Xiaobao Yang, Biao Jiang

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

ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells

In the present study, we asked whether ALK inhibition affects autophagy, and whether this may influence treatment response. Whereas the impact of targeted therapies on autophagic activity previously have been assessed by surrogate marker proteins such as LC3B, we here thoroughly examined effects on functional autophagic activity, i.e. on the sequestration and degradation of autophagic cargo, in addition to autophagic markers. Interestingly, the ALK inhibitor Ceritinib decreased mTOR activity and increased GFP-WIPI1 dot formation in H3122 and H2228 EML4-ALK+ lung cancer cells, suggesting autophagy activation. Moreover, an mCherry-EGFP-LC3B based assay indicated elevated LC3B carrier flux upon ALK inhibition. In accordance, autophagic cargo sequestration and long-lived protein degradation significantly increased upon ALK inhibition. Intriguingly, autophagic cargo flux was dependent on VPS34 and ULK1, but not LC3B. Co-treating H3122 cells with Ceritinib and a VPS34 inhibitor or Bafilomyci..... READ ARTICLE

Scientific Reports DOI:10.1038/s41598-021-87966-6

Authors: Anna M. Schläfli, Igor Tokarchuk, Sarah Parejo, Susanne Jutzi, Sabina Berezowska, Nikolai Engedal, Mario P. Tschan

Pre-ClinicalKirk SmithApril 27, 2021ceritinib, mTOR, EML4-ALK+, VPS34 inhibitor, Bafilomycin A1, autophagy

Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling. READ ARTICLE

Cell DOI:10.1016/j.cell.2021.03.031

Authors: Asmin Tulpule, Juan Guan, Dana S Neel, Hannah R Allegakoen, Yone Phar Lin, David Brown, Yu-Ting Chou, Ann Heslin, Nilanjana Chatterjee, Shriya Perati, Shruti Menon, Tan A Nguyen, Jayanta Debnath, Alejandro D Ramirez, Xiaoyu Shi, Bin Yang, Siyu Feng, Suraj Makhija, Bo Huang, Trever G Bivona

Activated ALK Cooperates with N-Myc via Wnt/β-Catenin Signaling to Induce Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis, and there is a critical need for novel therapeutic approaches. NEPC is associated with molecular perturbation of several pathways, including amplification of MYCN. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the pathogenesis of neuroblastoma and other malignancies where it cooperates with N-Myc. We previously identified the first case of ALK F1174C-activating mutation in a patient with de novo NEPC who responded to the ALK inhibitor, alectinib. Here, we show that coactivation of ALK and N-Myc (ALK F1174C/N-Myc) is sufficient to transform mouse prostate basal stem cells into aggressive prostate cancer with neuroendocrine differentiation in a tissue recombination model. A novel gene signature from the ALK F1174C/N-Myc tumors was associated with poor outcome in multiple human prostate cancer datasets. ALK F1174C and ALK F1174C/N-Myc tumors displayed activat..... READ ARTICLE

Cancer Research DOI:10.1158/0008-5472.CAN-20-3351

Authors: Kenji Unno, Zachary R. Chalmers, Sahithi Pamarthy, Rajita Vatapalli, Yara Rodriguez, Barbara Lysy, Hanlin Mok, Vinay Sagar, Huiying Han, Young A. Yoo, Sheng-Yu Ku, Himisha Beltran, Yue Zhao and Sarki A. Abdulkadir

Simultaneous Identification of EGFR,KRAS,ERBB2, and TP53 Mutations in Patients with Non-Small Cell Lung Cancer by Machine Learning-Derived Three-Dimensional Radiomics

Multiple genetic mutations are associated with the outcomes of patients with non-small cell lung cancer (NSCLC) after using tyrosine kinase inhibitor, but the cost for detecting multiple genetic mutations is high. Few studies have investigated whether multiple genetic mutations can be simultaneously detected based on image features in patients with NSCLC. We developed a machine learning-derived radiomics approach that can simultaneously discriminate the presence of EGFR, KRAS, ERBB2, and TP53 mutations on CT images in patients with NSCLC. These findings suggest that machine learning-derived radiomics may become a noninvasive and low-cost method to screen for multiple genetic mutations in patients with NSCLC before using next-generation sequencing tests, which can help to improve individualized targeted therapies. READ ARTICLE

Cancers DOI:10.3390/cancers13081814

Authors: Tiening Zhang, Zhihan Xu, Guixue Liu, Beibei Jiang, Geertruida H. de Bock, Harry J. M. Groen, Rozemarijn Vliegenthart, Xueqian Xie

Pre-ClinicalKirk SmithApril 1, 2021NSCLC, Radiomics

EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells.

Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes.EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. Methods:Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated β-galactosidase (SA-β-gal)..... READ ARTICLE

BMC Cancer DOI:10.1186/s12885-021-07905-6

Authors: Miyanaga A, Matsumoto M, Beck JA, Horikawa I, Oike T, Okayama H, Tanaka H, Burkett SS, Robles AI, Khan M, Lissa D, Seike M, Gemma A, Mano H, Harris CC

PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer

Study Proposes proposes PI3Kβ as a novel regulator of ALKi resistance in ALK-rearranged lung cancer cells, showing efficacy even in aggressive TP53 mutant and mesenchymal cells. Given that multiple salvage signals are activated upon resistance to ALKi, the co-targeting of PI3Kβ may provide a promising therapy option as PI3Kβ acts as a common effector of multiple salvage pathways, including EGFR, autophagy and GPCRs. Importantly, we found that co-targeting of PI3Kβ showed reduced toxicity in normal lung epithelial cells when compared with co-targeting of EGFR, possibly providing for a relatively safe clinical direction to treat ALK-rearranged tumors. READ ARTICLE

BioRxIV DOI:10.1101/2021.03.18.435801

Authors: Sarang S. Talwelkar, Mikko I. Mäyränpää, Julia Schüler, Nora Linnavirta, Annabrita Hemmes, Simone Adinolfi, Matti Kankainen, Wolfgang Sommergruber, Anna-Liisa Levonen, Jari Räsänen, Aija Knuuttila, Emmy W. Verschuren, Krister Wennerberg

Pre-Print, Pre-ClinicalKirk SmithMarch 18, 2021PI3Kβ inhibition

Efficacy of combination treatment using YHO-1701, an orally active STAT3 inhibitor, with molecular-targeted agents on cancer cell line

Investigation into efficacy of combination treatment using YHO-1701, an orally active STAT3 inhibitor, with molecular-targeted agents on cancer cell lines. Studied the contribution of YHO-1701 to enhance the antitumor properties of alectinib, YHO-1701 was combined with different doses of alectinib. The combination therapy of YHO-1701 with alectinib was found to be significantly effective against H2228 xenografts under both conditions, where the tumors remained larger and almost stable throughout the experimental period with alectinib monotherapy. This indicates that YHO-1701 offers an ideal and practical combination efficacy when used in combination with alectinib. Remarkably, in contrast with monotherapies, YHO-1701 plus alectinib diminished survivin levels in tumor tissues, suggesting that the superior antitumor activity of this combination is, at least partially, attributable to this downregulation. Regarding survivin, some studies have shown its potential characteristics as a usefu..... READ ARTICLE

Scientific reports DOI: 10.1038/s41598-021-86021-8

Authors: Keisuke Taniguchi, Hiroaki Konishi, Akiko Yoshinaga, Momomi Tsugane, Hiroyuki Takahashi, Fukiko Nishisaka, Yoshiyuki Shishido, Akira Asai

Pre-ClinicalKirk SmithMarch 1, 2021STAT3 inhibitor, combination treatment

Targeting a neoantigen derived from a common TP53 mutation

Like our ALK vaccine, this group had worked on a TP53 vaccine, using a similar technique Dr. Chairle described for ALK. TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen–A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: a bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target..... READ ARTICLE

Science DOI: 10.1126/science.abc8697

Authors: Emily Han-Chung Hsiue, Katharine M. Wright, Jacqueline Douglass, Michael S. Hwang, Brian J. Mog, Alexander H. Pearlman, Suman Paul, Sarah R. DiNapoli, Maximilian F. Konig, Qing Wang, Annika Schaefer, Michelle S. Miller, D. Skora, P. Aitana Azurmend, Michael B. Murphy, Liu, Evangeline Watson, Yana Li, M. Pardoll, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein,Sandra B. Gabelli, Shibin Zhou

Pre-ClinicalKirk SmithMarch 1, 2021TP53, T cells

Discovery of a PROTAC targeting ALK with in vivo activity

Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy. In this study, a series of ALK degraders were designed and synthesized. The degraders were developed through the conjugation of LDK378 and CRBN E3 ubiquitin ligase ligands. Among all the molecules, compound B3 showed potent selective inhibitory activity to ALK and can decrease the cellular levels of ALK fusion proteins in a concentration- and time-dependent manner in H3122 cell line. Meanwhile, B3 showed improved anticancer activity in vitro comparing with LDK378 and the antiproliferative activity to xenograft tumor model was acceptable. All the results demonstrated that ALK degrader B3 with in vitro and in vivo anti-cancer activities was valua..... READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2020.113150

Authors: Guoyi Yan, Xinxin Zhong, Lin Yue, Chunlan Pu, Huifang Shan, Suke Lan, Meng Zhou, Xueyan Hou, Jie Yang and Rui Li

Pre-ClinicalKirk SmithFebruary 15, 2021ALK, Degrader, Oral anticancer bioactivities, PROTAC

Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

Potent inhibitors of ALK are highly desired because of the occurrence of drug resistance. We herein firstly report the development of a rationally designed inhibitor, Con B-1, which can covalently bind to Cys1259, a cysteine located outside the ALK active site by linking a warhead with Ceritinib through a 2,2′-Oxybis(ethylamine) linker. The in vitro and in vivo assays showed ConB-1 is a potent selective ALKi with low toxicity to normal cells. In addition, the molecule showed significant improvement of anticancer activities and potential antidrug resistant activity compared with Ceritinib, demonstrating the covalent inhibitor of ALK can be a promising drug candidate for the treatment of NSCLC. This work may provide a novel perspective on the design of covalent inhibitors. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.0c01707

Authors: Guoyi Yan, Xinxin Zhong, Chunlan Pu, Lin Yue, Huifang Shan, Suke Lan, Meng Zhou, Xueyan Hou, Jie Yang, Deyu Li, Shilong Fan, and Rui Li

Pre-ClinicalKirk SmithJanuary 20, 2021Cells, Inhibitors, Inhibition, Peptides and proteins, Molecules

Evolutionary analyses guide selection of model systems to investigate proto-oncogene function in ALK and LTK

Model systems to investigate oncogene-driven cancer have played an essential role in the development of therapies for cancer. However, not all systems are appropriate for all therapeutic targets. Knowing where and when proto-oncogenes and their interactors originated in evolutionary history is key to understanding which organisms can serve as models. Here we investigate two tyrosine kinase receptors that underlie tumorigenesis in cancer: anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK). In Drosophila melanogaster, Caenorhabitis elegans, and Homo sapiens, the discovery of putative ligands Jeb, Hen-1, and AUG has the potential to accelerate the development of novel therapeutics. However, homology of these ligands and receptors is unclear. We performed an exhaustive search for their homologs spanning the metazoan tree of life. Jeb and Hen-1 were restricted to species that diverged prior to the origin of all vertebrates. No non-vertebrate species had ligands orthologous..... READ ARTICLE

Genome Biology and Evolution DOI:10.1101/795468

Authors: Alex Dornburg, Zheng Wang, Junrui Wang, Elizabeth S Mo, Francesc López-Giráldez, Jeffrey P Townsend

Pre-ClinicalKirk SmithJanuary 1, 2021Proto-oncogene function, ALK, leukocyte tyrosine kinase (LTK)

The effect of metformin in EML4-ALK+ lung cancer alone and in combination with crizotinib in cell and rodent models

Cell based studies have suggested that the diabetes drug metformin may combine with the anaplastic lymphoma kinase receptor (ALK) inhibitor crizotinib to increase ALK positive lung cancer cell killing and overcome crizotinib resistance. We therefore tested metformin alone and in combination with crizotinib in vivo, by employing a xenograft mouse model of ALK positive lung cancer. We found that 14 days of daily oral metformin (100 mg/kg) alone had a moderate but statistically significant effect on tumour growth suppression, but in combination with crizotinib, produced no greater tumour suppression than crizotinib (25 mg/kg) alone. We also reassessed the effect of metformin on EML4-ALK positive lung cancer (H3122) cell viability. Although metformin alone did have a moderate effect on cell viability (30% suppression) this was only at a clinically irrelevant concentration (5 mM) and there was no additive effect with cytotoxic concentrations of crizotinib. Moreover, metformin did not overco..... READ ARTICLE

Biochemical Pharmacology DOI:10.1016/j.bcp.2020.114345

Authors: A.R. Bland, N. Shrestha, R.L. Bower, R.J. Rosengren, J.C. Ashton

Pre-ClinicalKirk SmithJanuary 1, 2021Crizotinib, Metformin, EML4-ALK+ lung cancer

APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number..... READ ARTICLE

BioRxIV DOI:10.1101/2021.01.20.426852

Authors: Hideko Isozaki, Ammal Abbasi, Naveed Nikpour, Adam Langenbucher, Wenjia Su,
Marcello Stanzione, Heidie Frisco Cabanos, Faria M. Siddiqui, Nicole Phan, Pégah Jalili,
Sunwoo Oh, Daria Timonina, Samantha Bilton, Maria Gomez-Caraballo, Hannah L.
Archibald, Varuna Nangia, Kristin Dionne, Amanda Riley, Matthew Lawlor, Mandeep Kaur Banwait, Rosemary G. Cobb, Lee Zou, Nicholas J. Dyson, Christopher J. Ott, Cyril
Benes, Gad Getz, Chang S. Chan, Alice T. Shaw, Jessica J. Lin, Lecia V. Sequist,
Zofia Piotrowska, Jeffrey A. Engelman, Jake June-Koo Lee, Yosef Maruvka, Rémi
Buisson, Michael S. Lawrence, Aaron N. Hata

Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation

Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. We propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD. READ ARTICLE

Molecular Psychiatry DOI: 10.1038/s41380-020-01003-y

Authors: Jisu Park, Hyunwoo Choi, Young Doo Kim, Seo-Hyun Kim, Youbin Kim, Youngdae Gwon, Dong Young Lee, Sung-Hye Park, Won Do Heo & Yong-Keun Jung

Pre-ClinicalKirk SmithJanuary 1, 2021ALK, tau, Alzheimer's disease, AD

Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression.

These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC. READ ARTICLE

Clinical Cancer Research DOI: 10.1158/1078-0432.ccr-20-2853

Authors: Azusa Tanimoto, Shingo Matsumoto, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Akihiro Nishiyama, Kiyotaka Yoh, Takaya Ikeda, Naoki Furuya, Kazumi Nishino, Yuichiro Ohe, Koichi Goto, Seiji Yano

Pre-ClinicalKirk SmithDecember 1, 2020ALK rearrangement, alectinib, p53, Noxa, Mcl-1, apoptosis

Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapymediated activation of NF-kB signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy. READ ARTICLE

BioRxIV DOI:10.1101/2020.12.18.423280

Authors: Manasi K. Mayekar, View ORCID ProfileDeborah R. Caswell, Natalie I. Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, D. Lucas Kerr, Julia K. Rotow, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanjo, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nnennaya Kanu, Nicholas McGranahan, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever G. Bivona, Charles Swanton

Pre-Clinical, Pre-PrintKirk SmithDecember 1, 2020ALK, EGFR, NFkB, APOBEC deaminases

EML4-ALK-mediated Activation of the JAK2-STAT Pathway is Critical for Non-small Cell Lung Cancer Transformation

Aberrant expression of EML4-ALK leads to JAK2-STAT signaling pathway activation, an essential part of the development of non-small cell lung cancer. READ ARTICLE

BMC Pulmonary Medicine DOI: https://doi.org/10.1186/s12890-021-01553-z

Authors: Ying Li, Yongwen Li, Hongbing Zhang, Ruifeng Shi, Zihe Zhang, Hongyu Liu, Jun Chen

Pre-ClinicalKirk SmithDecember 1, 2020EML4-ALK, JAK2-STAT pathway, transformation, NSCLC

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Introduction: Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy. Conclusions: Uncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.10.156

Authors: Weihua Li, Lei Guo, Yutao Liu, Lin Dong, Lin Yang, Li Chen, Kaihua Liu, Yang Shao, Jianming Ying