Association between circulating tumor DNA burden and disease burden in patients with ALK-positive lung cancer

Plasma genotyping is an emerging approach for the identification of genetic alterations mediating resistance to ana-plastic lymphoma kinase (ALK)–targeted therapy. The authors reviewed plasma genotyping and imaging findings to assess the correla-tion between circulating tumor DNA (ctDNA) burden and disease burden in patients with ALK-positive lung cancer. The authors analyzed 97 plasma specimens from 75 patients with ALK-positive lung cancer to identify ALK and non-ALK alterations. In patients with ALK-positive lung cancer, the maximum plasma alteration AF and maximum ALK alteration AF correlate with the extrathoracic burden of disease and are more predictive of tumor burden com-pared with the ALK fusion AF alone. READ ARTICLE

Cancer DOI:10.1002/cncr.33118

Authors: Eric W. Zhang , Ibiayi Dagogo-Jack MD, Anderson Kuo MD, PhD, Marguerite M. Rooney BSc, Alice T. Shaw MD, PhD, Subba R. Digumarthy MD

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

Efficacy of lorlatinib in lung carcinomas carrying distinct ALK translocation variants: The results of a single-center study

Background: Lorlatinib is a novel potent ALK inhibitor, with only a few studies reporting the results of its clinical use. Methods: This study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements, who had 2 ( n = 5), 1 ( n = 26) or none ( n = 4) prior tyrosine kinase inhibitors and received lorlatinib mainly within the compassionate use program. Results: Objective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively; brain metastases were particularly responsive to the treatment (OR: 22/27 (81%); DC: 27/27 (100%)). Median progression free survival (PFS) was estimated to be 21.8 months, and median overall survival (OS) approached to 70.1 months. Only 4 out of 35 patients experienced no adverse effects; two of them were the only subjects who had no clinical benefit from lorlatinib. PFS and OS in the no-adverse-events lorlatinib users were strikingly lower as compared..... READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2021.101121

Authors: Sergey V. Orlov, Aglaya G. Iyevleva, Elena A. Filippova, Alexandra M. Lozhkina, Svetlana V. Odintsova, Tatiana N. Sokolova, Natalia V. Mitiushkina, Vladislav I. Tiurin, Elena V. Preobrazhenskaya, Alexandr A. Romanko, Alexandr S. Martianov, Alexandr O. Ivantsov, Svetlana N. Aleksakhina, Alexandr V. Togo, Evgeny N. Imyanitov.

Guidelines for clinical practice of ALK fusion detection in non-small-cell lung cancer: a proposal from the Chinese RATICAL study group

The presence of anaplastic lymphoma kinase (ALK) rearrangement defines a molecular subtype of non-small-cell lung cancer (NSCLC). ALK inhibitors (ALKIs) confer significant clinical benefits in patients with ALK-positive advanced NSCLC; therefore, it is of great clinical significance to select accurate, rapid, and appropriate ALK testing methods to screen for patients who are suitable for anti-ALK treatment. In recent years, great progress has been made in the development and clinical application of ALKIs, as well as in our understanding of acquired drug resistance mechanisms. Meanwhile, new ALK companion diagnostic platforms have been developed and applied in clinical practice. Although many studies have shown that there is a high rate of concordance among these platforms, new problems continue to appear during testing. To maximize the benefit for patients, accurate testing results can be obtained by first selecting the appropriate testing method and then formulating, optimizing, and c..... READ ARTICLE

Journal of the National Cancer Center DOI:10.1016/j.jncc.2021.07.005

Authors: Wenbin Li, Jing Zhang, Zhijie Wang, Lin Li, Jie Ma, Xiaoyang Zhou, Jie Wang, Zhiyong Liang, Jianming Ying,

Review Paper, group3Kirk SmithJuly 30, 2021ALK, Non-small-cell lung cancer, Detection method

Drug interaction profile of TKI alectinib allows effective and safe treatment of ALK+ lung cancer in the kidney transplant recipient

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer.Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs h..... READ ARTICLE

International Immunopharmacology DOI:10.1016/j.intimp.2021.108012

Authors: Ondrej Bilek, Milos Holanek, Jan Jurica, Sona Stepankova, Jiri Vasina, Iveta Selingerova, Alexandr Poprach, Simona Borilova, Tomas Kazda, Igor Kiss, Lenka Zdrazilova-Dubska

Brigatinib versus Crizotinib in Anaplastic Lymphoma Kinase (ALK) Inhibitor–Naive Advanced ALK-Positive Non–Small Cell Lung Cancer: Final Results of the Phase 3 ALTA-1L Trial

In the phase 3 ALTA-1L study of brigatinib in anaplastic lymphoma kinase (ALK) inhibitor–naive advanced ALK+ NSCLC, brigatinib demonstrated superior progression-free survival (PFS) versus crizotinib in 2 planned interim analyses. We report final efficacy, safety, and exploratory results. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.07.035

Authors: D. Ross Camidge, Hye Ryun Kim, Myung-Ju Ahn, James CH. Yang, Ji-Youn Han, Maximilian J. Hochmair, Ki Hyeong Lee, Angelo Delmonte, Maria Rosario Garcia Campelo, Dong-Wan Kim, Frank Griesinger, Enriqueta Felip, Raffaele Califano, Alexander I. Spira, Scott N. Gettinger, Marcello Tiseo, Huamao M. Lin, Yuyin Liu, Florin Vranceanu, Huifeng Niu, Pingkuan Zhang, Sanjay Popat

Dramatic response to alectinib in a patient with ALK-rearranged squamous cell lung cancer

Lung cancers with anaplastic lymphoma kinase (ALK) rearrangements are highly sensitive to treatment with ALK tyrosine kinase inhibitors (TKIs). Due to the very low rate of patients with squamous cell carcinoma enrolled in clinical trials, the efficacy of ALK inhibitors in patients with ALK-rearranged squamous cell carcinoma in the lung remains unclear. Herein, we present the case of a 70-year-old female patient with squamous cell lung cancer harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. The patient was treated with the ALK-TKI alectinib as first-line regimen and achieved a dramatic response without severe adverse events, demonstrating alectinib as a therapeutic option for patients with ALK-positive squamous cell carcinoma. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14092

Authors: Jun Shiihara,Fumiyoshi Ohyanagi,Hikari Amari,Minemichi Toda,Hiroki Tahara,Motoi Yuzawa,Yuki Maeda,Motoko Nomura,Yoshiko Mizushina,Yoshiaki Nagai,Hiromitsu Ohta,Yasuhiro Yamaguchi

Case StudyKirk SmithJuly 29, 2021ALK, squamous cell carcinoma, EML4-ALK. fusion gene, alectinib

Treatment Strategy of Lung Adenocarcinoma with Concomitant EGFR Mutation and ALK Rearrangement

The incidence of synchronous mutations of Epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) was low. Now clinical experience is still insufficient. Simultaneously the treatment of brain metastasis hemorrhage in the acute phase with lung cancer is still controversial. We described the clinical treatment strategy of a patient with synchronous mutations of EGFR and ALK.We found that the tumor was well controlled. Progression-free survival (PFS)1 was 4 months, PFS2 was 3 months, PFS3 was 5 months, PFS4 was 5 months, and PFS5 was 9 months. At present, the patient still maintains partial response (PR) status. READ ARTICLE

Research Square DOI:10.21203/rs.3.rs-718876/v1

Authors: Li Li , Wei Liu , Chunhua Xu, Jue Zou

Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non–Small Cell Lung Cancer

In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. ClinicalTrials.gov Identifier: NCT02186847 READ ARTICLE

JAMA: Journal of American Medical Association DOI:10.1001/jamaoncol.2021.2318

Authors: Heath Skinner, MD,PhD; Chen Hu, PhD; Theodoros Tsakiridis, MD, PhD; Rafael Santana-Davila, MD; Bo Lu, MD; Jeremy J. Erasmus, MD; Anthony J. Doemer, MS; Gregory M. M. Videtic, MD; James Coster, MD; Alex Xuezhong Yang, MD; Richard Y. Lee, MD, PhD; Maria Werner-Wasik, MD; Philip E. Schaner, MD, PhD; Steven E. McCormack, MD; Benjamin T. Esparaz, MD; Ronald C. McGarry, MD,PhD; Jose Bazan, MD; Timothy Struve, MD; Rebecca Paulus, BS and Jeffrey D. Bradley, MD

Clinical Trials, group4Kirk SmithJuly 29, 2021NSCLC, metformin, chemoradiation

Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study

Our previously published findings reported that local consolidative therapy (LCT) with radiotherapy or surgery improved progression-free survival (PFS) and delayed new disease in patients with oligometastatic non–small-cell lung cancer (NSCLC) that did not progress after front-line systemic therapy. Herein, we present the longer-term overall survival (OS) results accompanied by additional secondary end points. In patients with oligometastatic NSCLC that did not progress after front-line systemic therapy, LCT prolonged PFS and OS relative to MT/O. READ ARTICLE

Journal of Clinical Oncology DOI: 10.1200/JCO.19.00201

Authors: Daniel R. Gomez, Chad Tang, Jianjun Zhang, George R. Blumenschein Jr, Mike Hernandez, J. Jack Lee, Rong Ye, David A. Palma, Alexander V. Louie, D. Ross Camidge, Robert C. Doebele, Ferdinandos Skoulidis, Laurie E. Gaspar, James W. Welsh, Don L. Gibbons, Jose A. Karam, Brian D. Kavanagh, Anne S. Tsao, Boris Sepesi, Stephen G. Swisher, John V. Heymach

Real-World OutcomesKirk SmithJuly 25, 2021ALK, tau, Alzheimer's disease (AD)

Mutations

A video on "what is a mutation" by Vanderbilt University Medical Center. Basic background with clear graphic depictions. SEE VIDEO

Vanderbilt University Medical Center

Video, group4Kirk SmithJuly 24, 2021mutations

Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients

The treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC) remains a challenge. We compared the safety and efficacy of lorlatinib and alectinib in patients with ALK-p ALK-inhibitor‒naïve advanced NSCLC (in overall participants and in the Asian and non-Asian subgroups). The results showed that in the overall participant group, the efficacy of lorlatinib and alectinib was not significantly different in terms of progression-free survival (PFS) and overall survival (OS). Although in the Asian subgroup, PFS was not significantly different upon treatment with lorlatinib or alectinib, in the non-Asian subgroup, PFS was significantly better in response to lorlatinib than with alectinib. Grade 3 or higher adverse events in the overall participant group were significantly more frequent with lorlatinib than with alectinib. These results will provide valuable information that would enable the improvement of treatment strategies for ALK-p ALK-inhibitor‒naïve advanced NSCLC. READ ARTICLE

Cancers DOI:10.3390/cancers13153704

Authors: Koichi Ando, Ryo Manabe,Yasunari Kishino, Sojiro Kusumoto,Toshimitsu Yamaoka, Akihiko Tanaka, Tohru Ohmori and Hironori Sagara

Real-World Outcomes, group4Kirk SmithJuly 23, 2021alectinib, ALK rearrangement, lorlatinib

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

Association of anaplastic lymphoma kinase variants and alterations with ensartinib response duration in non-small cell lung cancer

Here, we aimed to assess the association of ALK variants and alterations with ensartinib response duration in NSCLC, and explore the potential value of computed tomography (CT) radiomic features in predicting progression-free survival (PFS). We enrolled 88 patients with identified ALK variant NSCLC in a multicenter phase 2 trial, and assessed the impact of ALK variants and secondary ALK alterations on the clinical outcome (response duration) of patients receiving ensartinib. Our study showed that secondary ALK alterations were adversely associated with ensartinib efficacy, and that ALK variants might not correlate with PFS. The quantitative radiomic signature provided added prognostic prediction value to the clinicopathological features. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14083

Authors: Donghui Hou, Xiaomin Zheng, Wei Song, Xiaoqing Liu, Sicong Wang, Lina Zhou, Xiuli Tao, Lv Lv, Qi Sun, Yujing Jin,Zewei Zhang, Lieming Ding, Ning Wu, Shijun Zhao

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

Real-world insights into patients with advanced NSCLC and MET alterations

Heterogeneous treatments reflect the changing landscape and availability of new treatments, as well as the high unmet medical need in older, METex14 patients who had more advanced disease at diagnosis. MET-targeted therapies could be beneficial in patients with these rare MET alterations. RE AD ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.06.015

Authors: Marisa Bittonia James Chih-Hsin Yang, Jin-Yuan Shih, Nir Peled, Egbert F. Smite, D. Ross Camidge, Rajeswara Rao Arasada, Dina Okseng, Emmanuelle Boutmy, Christopher Stroh, Andreas Johne, David P. Carbonea and Paul K. Paik

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