F-circEA1 regulates cell proliferation and apoptosis through ALK downstream signaling pathway in non-small cell lung cancer

Studies have confirmed that circular RNA (circRNA) has a stable closed
structure, which plays an important role in the progression of tumors.
Cancers with positive fusion genes can produce associated fusion circRNA
(F-cirRNA). However, there are no reports concerning a role for
F-circRNA of the echinoderm microtubule associated-protein like
4-anaplastic lymphoma kinase variant 1 (EML4-ALK1) in non-small cell
lung cancer (NSCLC). Our study confirmed the existence of fusion circEA1
(F-circEA1) in NCI-H3122 cells (carrying the EML4-ALK1 gene), F-circEA1
was expressed both in the cytoplasm and nucleus as determined by
fluorescence in situ hybridization (FISH) and Sanger sequencing. CCK8
and transwell assays showed that F-circEA1 was beneficial to cell
proliferation, metastasis, and invasion. Overexpression of F-circEA1 can
also promote cell proliferation, migration and invasion in A549 and
SPCA1 cells (non-small cell lung cancer cell line not carrying the
EML4-ALK1 gene). Int..... READ ARTICLE

Human Cell DOI:10.1007/s13577-021-00628-7

Authors: Yinping Huo, Tangfeng Lv, Mingxiang Ye, Suhua Zhu, Jiaxin Liu, Hongbing Liu & Yong Song

Pre-Clinical, group2Kirk SmithOctober 11, 2021F-circEA1, EML4-ALK, NSCLC, Apoptosis

Mapping the Phospho-dependent ALK Interactome to Identify Novel Components in ALK Signaling

Protein-protein interactions (PPIs) play essential roles in Anaplastic Lymphoma Kinase (ALK) signaling. Systematic characterization of ALK interactors helps elucidate novel ALK signaling mechanisms and may aid in the identification of novel therapeutics targeting related diseases. In this study, we used the Mammalian Membrane Two-Hybrid (MaMTH) system to map the phospho-dependent ALK interactome. By screening a library of 86 SH2 domain-containing full length proteins, 30 novel ALK interactors were identified. Many of their interactions are correlated to ALK phosphorylation activity: oncogenic ALK mutations potentiate the interactions and ALK inhibitors attenuate the interactions. Among the novel interactors, NCK2 was further verified in neuroblastoma cells using co-immunoprecipitation. Modulation of ALK activity by addition of inhibitors lead to concomitant changes in the tyrosine phosphorylation status of NCK2 in neuroblastoma cells, strongly supporting the functionality of the ALK/NCK2 interaction. Our study provides a resource list of potential novel ALK signaling components for further study. READ ARTICLE

Journal of Molecular Biology DOI:10.1016/j.jmb.2021.167283

Authors: Farzaneh Aboualizadeh, ZhongYao, Jikui Guan, Luka Drecun, Shivanthy Pathmanathan, Jamie Snider, Ganesh Umapathy, Max Kotlyar, Igor Jurisica, Ruth Palmer and Igor Stagljar

Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-β signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with th..... READ ARTICLE

Cancer Cell DOI:10.1016/j.ccell.2021.09.003

Authors: Hu H, Piotrowska Z, Hare PJ, Chen H, Mulvey HE, Mayfield A, Noeen S, Kattermann K, Greenberg M, Williams A, Riley AK, Wilson JJ, Mao YQ, Huang RP, Banwait MK, Ho J, Crowther GS, Hariri LP, Heist RS, Kodack DP, Pinello L, Shaw AT, Mino-Kenudson M, Hata AN, Sequist LV, Benes CH, Niederst MJ, Engelman JA.

Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells

Advanced NSCLC patients harboring EML4-ALK and CCDC6-RET rearrangements derive benefit from treatment with ALK and RET TKIs but not immune checkpoint inhibitors. New immunotherapeutic approaches, such as immunization against growth factors, can be of particular interest for combination treatment in these patients. Here, we investigated the effects of anti-EGF antibodies generated by vaccination (anti-EGF VacAbs), TKIs and combinations in EML4-ALK and CCDC6-RET NSCLC cell lines. We found that EGF and tumor growth factor alpha (TGFα) significantly decreased the antiproliferative activity of the RET inhibitor BLU-667 in CCDC6-RET cells and brigatinib, alectinib and crizotinib in EML4-ALK translocated cells. The addition of anti-EGF VacAbs reversed the effects of EGF and TGFα, potentiated the antitumor effects of the kinase inhibitors and delayed the appearance in vitro of resistant clones. Western blotting demonstrated that the combination of anti-EGF VacAbs with ALK or RET TKIs effective..... READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2020.100887

Authors: Jordi Codony-Servat, Silvia García-Roman, Miguel Ángel Molina-Vila, Jordi Bertran-Alamillo, Santiago Viteri, Erik d'Hondt, Rafael Rosell,

Pre-Clinical, group3Kirk SmithSeptember 21, 2021ALK, RET, anti-EGF VacAbs

Pharmacometric analyses of alectinib to facilitate approval of the optimal dose for the first-line treatment of anaplastic lymphoma kinase–positive non-small cell lung cancer

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib-failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one-compartment models with sequential zero/first-order input and first-order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment-naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression-free survival in treatment-naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of trea..... READ ARTICLE

CPT: Pharmacometrics & Systems Pharmacology DOI:10.1002/psp4.12702

Authors: Joy C. Hsu, Felix Jaminion, Elena Guerini, Bogdana Balas, Walter Bordogna, Peter N. Morcos, Nicolas Frey

Pre-Clinical, group3Kirk SmithSeptember 21, 2021Non-small cell lung cancer, ALK, Alectinib, Pharmacometric analyses, Optimal dose

BioID-Screening Identifies PEAK1 and SHP2 as Components of the ALK Proximitome in Neuroblastoma Cells

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is mutated in approximately 10% of pediatric neuroblastoma (NB). To shed light on ALK-driven signaling processes, we employed BioID-based in vivo proximity labeling to identify molecules that interact intracellularly with ALK. NB-derived SK-N-AS and SK-N-BE(2) cells expressing inducible ALK-BirA* fusion proteins were generated and stimulated with ALKAL ligands in the presence and absence of the ALK tyrosine kinase inhibitor (TKI) lorlatinib. LC/MS-MS analysis identified multiple proteins, including PEAK1 and SHP2, which were validated as ALK interactors in NB cells. Further analysis of the ALK-SHP2 interaction confirmed that the ALK-SHP2 interaction as well as SHP2-Y542 phosphorylation was dependent on ALK activation. Use of the SHP2 inhibitors, SHP099 and RMC-4550, resulted in inhibition of cell growth in ALK-driven NB cells. In addition, we noted a strong synergistic effect of combined ALK and SHP2 inhibition that was specific to ALK-driven NB cells, suggesting a potential therapeutic option for ALK-driven NB. READ ARTICLE

Journal of Molecular Biology

Authors: Ezgi Uçkun, Joachim T. Siaw, Jikui Guan, Vimala Anthonydhason, Johannes Fuchs, Georg Wolfstetter, Bengt Hallberg and Ruth H.Palmer

Pre-Clinical, group3Kirk SmithSeptember 17, 2021BirA*, signaling, SHP099, RMC-4550, lorlatinib

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients. READ ARTICLE

Nature DOI:10.1038/s41467-021-25728-8

Authors: Johannes Brägelmann, Carina Lorenz, Sven Borchmann, Kazuya Nishii, Julia Wegner, Lydia Meder, Jenny Ostendorp, David F. Ast, Alena Heimsoeth, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Marcel A. Dammert, Dennis Plenker, Sebastian Klein, Philipp Lohneis, Jianing Gu, Laura K. Godfrey, Jan Forster, Marija Trajkovic-Arsic, Thomas Zillinger, Mareike Haarmann, Alexander Quaas, Stefanie Lennartz, Marcel Schmiel, Joshua D’Rozario, Emily S. Thomas, Henry Li, Clemens A. Schmitt, Julie George, Roman K. Thomas, Silvia von Karstedt, Gunther Hartmann, Reinhard Büttner, Roland T. Ullrich, Jens T. Siveke, Kadoaki Ohashi, Martin Schlee & Martin L. Sos

Sensitivity of eight types of ALK fusion variant to alectinib in ALK-transformed cells

Tyrosine kinase inhibitors of anaplastic lymphoma kinase (ALK-TKIs) including alectinib have been the standard therapy against ALK fusion gene-positive non-small cell lung cancers (NSCLCs). Many ALK fusion variants have been identified in NSCLCs, and the predominant variants are echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) variant 1 (V1), V2 and V3a/b. However, there have been conflicting reports on the clinical responses of these variants to ALK-TKIs, and there are few reports on other less common ALK variants. To examine the influence of ALK variants on the efficacy of ALK-TKIs, we analyzed the sensitivity to alectinib of eight types of ALK variant: three major variants (V1, V2 and V3a) and five less common variants (V4; kinesin family member 5-ALK; kinesin light chain 1-ALK; striatin, calmodulin-binding protein-ALK; and tropomyosin-receptor kinase fused gene-ALK). Analysis was done by cell-free kinase assays using the recombinant proteins and by cell, growth assay..... READ ARTICLE

Anticancer Drugs DOI:10.1097/CAD.0000000000001249

Authors: Furugaki K, Harada N, Yoshimura Y.

Pre-Clinical, group3Kirk SmithSeptember 13, 2021alectinib, ALK, EML4, fusion, KIF5B, KLC1, lung cancer, STRN, TFG, variant

TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutation

Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of central nervous system (CNS) penetration and potency against wild-type (WT) 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 approv..... READ ARTICLE

Molecular Cancer Therapeutics DOI: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

Cycling cancer persister cells arise from lineages with distinct programs

Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell’s clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with..... READ ARTICLE

Nature DOI:10.1038/s41586-021-03796-6

Authors: Yaara Oren, Michael Tsabar, Michael S. Cuoco, Liat Amir-Zilberstein, Heidie F. Cabanos, Jan-Christian Hütter, Bomiao Hu, Pratiksha I. Thakore, Marcin Tabaka, Charles P. Fulco, William Colgan, Brandon M. Cuevas, Sara A. Hurvitz, Dennis J. Slamon, Amy Deik, Kerry A. Pierce, Clary Clish, Aaron N. Hata, Elma Zaganjor, Galit Lahav, Katerina Politi, Joan S. Brugge & Aviv Regev

Pre-Clinical, group3Kirk SmithAugust 11, 2021Watermelon library, lineage diversity and fate, models

Folate-Guided Protein Degradation by Immunomodulatory Imide Drug-Based Molecular Glues and Proteolysis Targeting Chimeras

Molecular glues and proteolysis targeting chimeras (PROTACs) are promising new therapeutic modalities. However, the lack of specificity for molecular glue- or PROTAC-mediated proteolysis in cancer cells versus normal cells raises potential toxicity concerns that will likely limit their clinical applications. Here, we developed a general strategy to deliver immunomodulatory imide drug (IMiD)-based molecular glues and PROTACs to folate receptor α (FOLR1)-positive cancer cells. Specifically, we designed a folate-caged pomalidomide prodrug, FA-S2-POMA, by incorporating a folate group as a caging and guiding element and validated its degradation effect on its neo-substrates in FOLR1-positive cancer cells in a FOLR1-dependent manner. We also developed a folate-caged pomalidomide-based anaplastic lymphoma kinase (ALK) PROTAC, FA-S2-MS4048, which effectively degraded ALK fusion proteins in cancer cells, again in a FOLR1-dependent manner. This novel approach provides a generalizable platform fo..... READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.1c00901

Authors: He Chen, Jing Liu, H. Ümit Kaniskan, Wenyi Wei, and Jian Jin

One-Step Polymerase Chain Reaction-Free Nanowire-Based Plasma Cell-Free DNA Assay to Detect EML4-ALK Fusion and to Monitor Resistance in Lung Cancer

Background: Next-generation sequencing has mostly been used for genotyping cell-free DNA (cfDNA) in plasma. However, this assay has several clinical limitations. We evaluated the clinical utility of a novel polymerase chain reaction–free nanowire (NW)-based plasma cfDNA assay for detecting ALK fusion and mutations. Conclusion: The newly developed simple NW-based cfDNA assay may be clinically applicable for rapid diagnosis of ALK fusion with its variant forms and early detection of resistance. READ ARTICLE

The Oncologist DOI:10.1002/onco.13902

Authors: Youngjoo Lee, Youngnam Cho, Eun Young Park, Seong-Yun Park, Kum Hui Hwang, Ji-Youn Han

Development and validation of UPLC–MS/MS method for the simultaneous quantification of anaplastic lymphoma kinase inhibitors, alectinib, ceritinib, and crizotinib in Wistar rat plasma...

Bromelain, the aqueous extract of pineapple, has been used as a food supplement with reported nutritional and therapeutic benefits. Bromelain has anti-cancer, anti-inflammatory, antithrombotic, and fibrinolytic effects. Anaplastic lymphoma kinase (ALK) inhibitors, including alectinib (ALC), ceritinib (CER), and crizotinib (CRZ), have been efficiently used in the management of non-small cell lung cancer (NSCLC). The solubility of ALC, CER, and CRZ is much higher at low acidic pH (pH 1) and it decreases as the pH increases affecting their absorption with a subsequent decrease in their bioavailability. It was thought that the intake of bromelain could result in a decrease in the bioavailability of ALC, CER, and CRZ due to bromelain-induced alkalizing effect following digestion. On the contrary, bromelain could possibly increase plasma exposure of the cited drugs due to its known muco-permeation enhancing effect. The therapeutic-anticancer effect of bromelain can be possibly increased/enha..... READ ARTICLE

Journal of Pharmaceutical and Biomedical Analysis DOI:10.1016/j.jpba.2021.114276

Authors: Hadir M. Maher, Aliyah Almomen, Nourah Z. Alzoman, Shereen M. Shehata, Ashwaq A. Alanazi

Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile

Proteolysis-targeting chimera (PROTAC) is an attractive technology in drug discovery. Canonically, targets act as a basic starting point in the most previous PROTAC design. Here, we designed degraders considering from the view of clinical benefits. With this novel design, Brigatinib was turned into a degrader SIAIS164018 and endowed with unique features. First, SIAIS164018 could degrade not only ALK fusion proteins in activating or G1202R-mutated form but also mutant EGFR with L858R + T790M, which are two most important targets in non-small-cell lung cancer. Second, SIAIS164018 strongly inhibited cell migration and invasion of Calu-1 and MDA-MB-231. Third and surprisingly, SIAIS164018 degrades several important oncoproteins involved in metastasis such as FAK, PYK2, and PTK6. Interestingly, SIAIS164018 reshuffled the kinome ranking profile when compared to Brigatinib. Finally, SIAIS164018 is orally bioavailable and well tolerated in vivo. SIAIS164018 is an enlightening degrader for us to excavate the charm of protein degradation. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.1c00373

Authors: Chaowei Ren, Ning Sun, Haixia Liu, Ying Kong, Renhong Sun, Xing Qiu, Jinju Chen, Yan Li, Jianshui Zhang, Yuedong Zhou, Hui Zhong, Qianqian Yin

Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

Gatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed hi..... READ ARTICLE

Precision Oncology DOI:10.1038/s41698-021-00203-1

Authors: Marianne Oulhen, Patrycja Pawlikowska, Tala Tayoun, Marianna Garonzi, Genny Buson, Claudio Forcato, Nicolò Manaresi, Agathe Aberlenc, Laura Mezquita, Yann Lecluse, Pernelle Lavaud, Charles Naltet, David Planchard, Benjamin Besse & Françoise Farace

Pre-Clinical, group4Kirk SmithJuly 16, 2021ALK, heterogeneity, single circulating tumor cells, RTK/RAS, EMT

Structural and functional analysis of lorlatinib analogs reveals roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

The treatment approach to advanced, ALK-positive non-small cell lung cancer (NSCLC) utilizing sequential ALK tyrosine kinase inhibitors (TKIs) represents a paradigm of precision oncology. Lorlatinib is currently the most advanced, potent and selective ALK tyrosine kinase inhibitor (TKI) in the clinic. However, tumors invariably acquire resistance to lorlatinib, and after sequential ALK TKIs culminating with lorlatinib, diverse refractory compound ALK mutations can emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations identified in patients after treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. By assessing a panel of lorlatinib analogs against compound ALK mutant in vitro and in vivo models, we identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R- versus I1171N/S/T-based compound ALK mutations. Structural analysis revealed that increased potency against compound mut..... READ ARTICLE

BioRxiv DOI:10.1101/2021.07.16.452681

Authors: Aya Shiba-Ishii, Ted W Johnson, Ibiayi Dagogo-Jack, Mari Mino-Kenudson, Theodore R Johnson, Ping Wei, Scott L Weinrich, Michele A McTigue, Makeba A Walcott, Linh Nguyen-Phuong, Kristin Dionne, Adam Acker, Lesli Kiedrowski, Andrew Do, Jennifer L Peterson, Jaimie L Barth, Beow Y Yeap, Justin F Gainor, Jessica J Lin, Satoshi Yoda, Aaron N Hata

Pharmacophore screening, molecular docking, ADMET prediction and MD simulations for identification of ALK and MEK potential dual inhibitors

Anaplastic lymphoma kinase (ALK) fusion gene is a common driver gene in non-small cell lung cancer (NSCLC). The activation of mitogen-activated protein kinase (MAPK) and other related signaling pathways cause the proliferation of cancer cells. Mitogen-activated protein kinase kinase (MAPKK, also known as MEK) is a member of the ALK-MAPK signaling cascade. Recent studies have found that the drug resistance in ALK-positive NSCLC is highly dependent on the activation of the MAPK pathway, and the combined inhibition of ALK and MEK can delay or even eliminate the resistance. In this work, dual ALK/MEK inhibitors were designed through computer-aided drug design (CADD). Ten million molecules from ZINC were screened through pharmacophore models, ADMET prediction and molecular docking. Finally, 35 hit compounds were obtained. Among them, compound 1 has the highest dual inhibitory potential. The results of molecular docking, ADMET prediction and molecular dynamics (MD) simulations show that comp..... READ ARTICLE

Journal of Molecular Structure DOI:10.1016/j.molstruc.2021.131066

Authors: Haoran Zhang, Lichuan Zhang, Chenglong Gao, Rilei Yu, Congmin Kang

Driver and novel genes correlated with metastasis of non-small cell lung cancer: A comprehensive analysis

Although mutations of genes are crucial events in tumorigenesis and development, the association between gene mutations and lung cancer metastasis is still largely unknown. The goal of this study is to identify driver and novel genes associated with non-small cell lung cancer (NSCLC) metastasis. Candidate genes were identified using a novel comprehensive analysis, which was based on bioinformatics technology and meta-analysis. Firstly, EGFR, KRAS, ALK, TP53, BRAF and PIK3CA were identified as candidate driver genes. Further meta-analysis identified that EGFR (Pooled OR 1.33, 95% CI 1.19, 1.50; P < .001) and ALK (Pooled OR 1.52, 95% CI 1.22, 1.89; P < .001) mutations were associated with distant metastasis of NSCLC. Besides, ALK (Pooled OR 2.40, 95% CI 1.71, 3.38; P < .001) mutation was associated with lymph node metastasis of NSCLC. In addition, thirteen novel gene mutations were identified to be correlated with NSCLC metastasis, including SMARCA1, GGCX, KIF24, LRRK1, LILRA4, OR2T10, E..... READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2021.153551

Authors: Yongfeng Wu, Heng Ni, Dexin Yang, Yuequn Niu, Kelie Chen, Jinming Xu, Fang Wang, Song Tang, Yu Shi, Honghe Zhang, Jian Hu, Dajing Xia, Yihua Wu

Pre-Clinical, group4Kirk SmithJuly 10, 2021Metastasis, Mutation, SMARCA1, EDNRB

Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents

Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brigatinib and similar to Ceritinib. Mechanism study revealed that the optimal compound 9e decreased the mitochondrial membrane potential and arrested NCI-H2228 cells in the G0/G1 phase, finally resulting in cellular apoptosis. It is interesting that 9e could effectively inhibit the migration of NCI-H2228 cells and may be a promising leading compound for chemotherapy of metastatic cancer. READ ARTICLE

Bioorganic & Medicinal Chemistry Letters DOI:10.1016/j.bmcl.2021.128253

Authors: Feng Wu, Han Yao, Wei Li, Niuniu Zhang, Yangyang Fan, Albert S.C. Chan, Xingshu Li, Baijiao An

SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy

The 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 patients treated with platinum-based chemotherapy had poor outcome (all patients were dead and the mean survival time was 12 months), compared to 72 months for patients with ALK inhibitor therapy. Furthermore, Five ALK-positive cases were analyzed by whole exome sequencing (WES) and via direct transcript counting using a digital probe-base (NanoString) to explore the driver genes. Deregulation of PI3K/AKT signaling pathway in ALK-positive lung cancer was demonstrated by WES analysis, and significantly increased mRNA of ALK, ROS1, MET, SPP1 and PI3K signaling pathway was identified by NanoString assay. The concordance between NanoString, IHC and FISH methodologies for detecting ALK fusion was 100%. Significant overexpression of SPP1 protein in ALK-positive lung cancer was confirmed by IHC compared to paired adjacent normal tissues and ALK-negative cancers. Thus we concluded that SPP1 overexpression is associated with poor outcomes for patients with ALK fusion lung cancer without receiving targeted therapy and PI3K/AKT/SPP1 pathway may become the promising targets in patients with aggressive lung cancer. 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 and Fei Pei

Pre-Clinical, group4Kirk SmithJuly 7, 2021SSP1, outcome, PI3K/AKT