This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies. READ ARTICLE
ESMO Open DOI: 10.1016/j.esmoop.2021.100172
Authors: V. Subbiah, S. Kuravi, S. Ganguly, D.R. Welch, C.J. Vivian, M.U. Mushtaq, A. Hegde, S. Iyer, A. Behrang, S.M. Ali, R.W. Madison, J.M. Venstrom, R.A. Jensen, J.P. McGuirk, H.M. Amin and R. Balusu
Read MoreThe screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive p..... READ ARTICLE
Scientific Reports DOI:10.1038/s41598-021-93484-2
Authors: Xiaolin Ji, Yan Liu, Fang Mei, Xinyang Li, Mengxue Zhang, Buwen Yao, Rui Wu, Jiangfeng You & Fei Pei
Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ~10%
of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most
non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage.
Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Cleavage inhibition results in the downregulation of an epithelial-to-mesenchymal transition (EMT) gene signature, with decreased nuclear localization and occupancy of b-catenin at EMT gene promoters. We further show that
cleavage is mediated by matrix metalloproteinase 9, whose genetic and pharmacologic inactivation inhibits
cleavage and decreases NB cell migration. Together, our results indicate a pivotal role for WT ALK ECD cleavage in NB pathogenesis, which may be harnessed for therapeutic benefit. READ ARTICLE
Cell Reports DOI:10.1016/J.CELREP.2021.109363
Authors: Hao Huang, Alexander Gont, Lynn Kee, Ruben Dries, Kathrin Pfeifer, Bandana Sharma, David N. Debruyne, Matthew Harlow, Satyaki Sengupta, Jikui Guan, Caleb M. Yeung, Wenchao Wang, Bengt Hallberg, Ruth H. Palmer, Meredith S. Irwin, Rani E. George
A series of novel anaplastic lymphoma kinase (ALK) degraders were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking two alectinib analogs (36 and 37) with pomalidomide through linkers of different lengths and types. The most promising degrader 17 possessed a high ALK-binding affinity and potent antiproliferative activity in the ALK-dependent cell lines and did not exhibit obvious cytotoxicity in ALK fusion-negative cells. More importantly, the efficacy of compound 17 in a Karpas 299 xenograft mouse model was further evaluated based on its ALK-sustained degradation ability in vivo. The reduction in tumor weight in the compound 17-treated group (10 mg/kg/day, I.V.) reached 75.82%, while alectinib reduced tumor weight by 63.82% at a dose of 20 mg/kg/day (P.O.). Taken together, our findings suggest that alectinib-based PROTACs associated with the degradation of ALK may have promising beneficial effects for treating ALK-driven malignancies. READ ARTICLE
Journal of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00270
Authors: Shaowen Xie, Yuan Sun, Yulin Liu, Xinnan Li, Xinuo Li, Wenyi Zhong, Feiyan Zhan, Jingjie Zhu, Hong Yao, Dong-Hua Yang, Zhe-Sheng Chen, Jinyi Xu and Shengtao Xu
Read MoreEpithelial–mesenchymal transition (EMT)—a fundamental process in embryogenesis and wound healing—promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. Combined metabolome and transcriptome analysis identified prolyl 4-hydroxylase α3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-β stimulation. Further, knockdown of P4HA3 diminished TGF-β-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-β stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-β-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer. READ ARTICLE
Communications Biology DOI: 10.1038/s42003-021-02323-7
Authors: Fumie Nakasuka, Sho Tabata, Takeharu Sakamoto, Akiyoshi Hirayama, Hiromichi Ebi, Tadaaki Yamada, Ko Umetsu, Maki Ohishi, Ayano Ueno, Hisatsugu Goto, Masahiro Sugimoto, Yasuhiko Nishioka, Yasuhiro Yamada, Masaru Tomita, Atsuo T. Sasaki, Seiji Yano and Tomoyoshi Soga
Read MoreHere, 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,
Read MoreGenome-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
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
Read MoreAlice Chou takes you back to high school and becomes your science teacher going over a special biology lesson on ALK Genetics. READ ARTICLE
Read MoreImmunogenic 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
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.
Read MoreExtracellular 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
Read MoreThe 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
Our findings provide novel insights into the underlying pathogenesis of LUAD. CTNNA2 mutation can change the immune microenvironment, thereby improving patient prognosis. The results also suggest that CTNNA2 may become a new biomarker and therapeutic target for LUAD in the future. READ ARTICLE
Frontiers in Pharmacology DOI: 10.3389/fphar.2021.645862
Authors: Wen Y., Lin A., Zhu W., Wei T., Luo P., Guo L. and Zhang J.
Read MoreDespite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dramatically reduced ALK and c-MET kinase-inhibitory potential. Furthermore, the prodrugs showed high stability in serum and release of crizotinib in an enzymatic nitroreductase-based cleavage assay was observed for prodrug A. The in vitro activity of both prodrugs was investigated against ALK- and c-MET-dependent or –overexpressing cells, revealing a distinct hypoxia-dependent activation for prodrug A. Finally, inhibition of c-MET phosphorylation and cell proliferation could also be proven in vivo. In summary of the theoretical, chemical and biological studies, prodrug derivatization of the 2-aminopyridine position can be considered as a promising strategy to reduce the side effects and improve the anticancer activity of crizotinib. READ ARTICLE
Bioorganic Chemistry DOI: 10.1016/j.bioorg.2020.103778
Authors: Bjoern Bielec, Hemma Schueffl, Alessio Terenzi, Walter Berger, Petra Heffeter, Bernhard K. Keppler and Christian R. Kowol
Read MoreOur data suggest that the aberrant expression of EML4-ALK leads to JAK2-STAT signaling pathway activation, which is essential for the development of non-small cell lung cancer. READ ARTICLE
BMC Pulmonary Medicine DOI:10.1186/s12890-021-01553-z
Authors: Ying Li, Yongwen Li, Hongbing Zhang, Ruifeng Shi, Zihe Zhang, Hongyu Liu, and Jun Chen
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, ALK inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of CNS penetration and potency against wild-type ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATP-binding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approved ALK inhibitors against wild-type ALK and many types of ALK resistance mutations, e.g. G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC50 <10 nmol/L) wild-type ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were ~66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against wild-type ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies. READ ARTICLE
Molecular Caner Therapeutics DOI: 10.1158/1535-7163.MCT-21-0221
Authors: Brion W. Murray, Dayong Zhai, Wei Deng, Xin Zhang, Jane Ung, Vivian Nguyen, Han Zhang, Maria Barrera, Ana Parra, Jessica Cowell, Dong J. Lee, Herve Aloysius and Evan Rogers
Read MoreHigh-risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of high-risk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients with activating ALK mutations. 8–10% of primary NB patients are ALK-positive, a figure that increases in the relapsed population. ALK is activated by the ALKAL2 ligand located on chromosome 2p, along with ALK and MYCN, in the “2p-gain” region associated with NB. Dysregulation of ALK ligand in NB has not been addressed, although one of the first oncogenes described was v-sis that shares > 90% homology with PDGF. Therefore, we tested whether ALKAL2 ligand could potentiate NB progression in the absence of ALK mutation. We show that ALKAL2 overexpression in mice drives ALK TKI-sensitive NB in t..... READ ARTICLE
EMBO DOI:10.15252/embj.2020105784
Authors: Marcus Borenäs, Ganesh Umapathy, Wei-Yun Lai, Dan E Lind, Barbara Witek, Jikui Guan, Patricia Mendoza-Garcia, Tafheem Masudi, Arne Claeys, Tzu-Po Chuang, Abeer El Wakil, Badrul Arefin, Susanne Fransson, Jan Koster, Mathias Johansson, Jennie Gaarder, Jimmy Van den Eynden, Bengt Hallberg and Ruth H Palmer
ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667Cmutant and ROS1 fusion-positive cancer. READ ARTICLE
Nature Communications DOI:10.1038/s41467-021-21396-w
Authors: Hayato Mizuta, Koutaroh Okada, Mitsugu Araki, Jun Adachi, Ai Takemoto, Justyna Kutkowska, Kohei Maruyama, Noriko Yanagitani, Tomoko Oh-hara, Kana Watanabe, Keiichi Tamai, Luc Friboulet, Kazuhiro Katayama, Biao Ma, Yoko Sasakura, Yukari Sagae, Mutsuko Kukimoto-Niino, Mikako Shirouzu, Satoshi Takagi, Siro Simizu, Makoto Nishio, Yasushi Okuno, Naoya Fujita, Ryohei Katayama
Using two genetically engineered mouse models (GEMMs), we find that EML4–ALK variant 1 can drive lung tumorigenesis and these murine tumors, as well as primary tumor-derived organoids, clearly show the condensates of EML4–ALK protein, further supporting the findings from in vitro study. Mutation of multiple aromatic residues in EML4 region significantly impairs the phase separation of EML4–ALK and dampens the activation of the downstream signaling pathways, especially the STAT3 phosphorylation. Importantly, it also significantly decreases cancer malignant transformation and tumor formation. These data together highlight an important role of phase separation in orchestrating EML4–ALK signaling and promoting tumorigenesis, which might provide new clues for the development of clinical therapeutic strategies in treating lung cancer patients with the EML4–ALK fusion. READ ARTICLE
Cell Discovery DOI: 10.1038/s41421-021-00270-5
Authors: Zhen Qin, Honghua Sun, Meiting Yue, Xinwen Pan, Liang Chen, Xinhua Feng, Xiumin Yan, Xueliang Zhu, Hongbin Ji
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