Targeted Therapy in a Young Adult With a Novel Epithelioid Tumor Driven by a PRRC2B-ALK Fusion

This case report describes an 18-year-old woman with an unusual epithelioid tumor of the omentum with a novel PRRC2B-ALK fusion. Although the atypical pathologic features raised significant diagnostic challenges, expression of CD30 on tumor cells and detection of an ALK rearrangement provided critical information for selecting targeted therapy in a patient not suitable for surgical resection. Despite an initially promising therapeutic response, the patient died. The efficacy of treatment was confirmed by the lack of viable tumor cells at autopsy. This case highlights the role of timely targeted therapy in patients with rare tumors and novel actionable molecular targets. READ ARTICLE

Journal of the National Comprehensive Cancer Network DOI:10.6004/jnccn.2021.7056

Authors: Ajay Gupta, Huifei Liu, Kathleen M. Schieffer, Selene C. Koo, Catherine E. Cottrell PhD, Elaine R. Mardis, Ryan D. Roberts and Nicholas D. Yeager MD

Case Study, group2Kirk SmithOctober 15, 2021PRRC2B-ALK, abdominal mass

Genetic and treatment profiles of patients with concurrent Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) mutations

EGFR and ALK alternations often contribute to human malignancies, including lung cancer. EGFR and ALK mutations are usually sensitive to EGFR-tyrosine kinase inhibitors (TKIs) and ALK-TKIs. Although generally mutually exclusive, these mutations do co-exist in rare cases. This study investigated the frequencies, clinical characteristics, therapeutic efficacies, and genetic profiles of lung cancer patients with EGFR and ALK co-mutations. ALK and EGFR mutations coincide at a relatively low frequency in lung cancer patients. ALK mutations developed either synchronously or heterochronously with EGFR mutations. Two ALK mutations (L1152R and STRN-ALK) may co-exist with EGFR mutations at a higher frequency than others. Most EGFR/ALK co-alteration patients (other than the EGFR/ALK L1152R type) can benefit from first line EGFR-TKIs. READ ARTICLE

BMC Cancer DOI:10.1186/s12885-021-08824-2

Authors: Xiaodan Yang, Jia Zhong, Zhuo Yu, Minglei Zhuo, Min Zhang, Rongrong Chen, Xuefeng Xia & Jun Zhao

Deep RNA sequencing revealed fusion junctional heterogeneity may predict crizotinib treatment efficacy in ALK-rearranged non-small cell lung cancer

Gene fusion variants in ALK-rearranged non-small cell lung cancer (NSCLC) may predict patient outcomes but previous results have been inconclusive. Fusion isoforms co-existing in the same tumor may affect targeted therapy efficacy but have not been investigated. Intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Song Z, Lian S, Mak S, Chow MZ, Xu C, Wang W, Keung HY, Lu C, Kebede FT, Gao Y, Cheuk W, Cho WCS, Yang M, Zheng Z.

New Advances in Liquid Biopsy Technologies for Anaplastic Lymphoma Kinase (ALK)—Positive Cancer

A new methodology of cancer testing, called “liquid biopsy”, has been under investigation in the past few years. It is based on blood tests that can be analyzed by novel genetics and bioinformatics tools, in order to detect cancer, predict or follow the response to therapies and understand the mechanisms of relapse. This technology is still experimental, yet it has sparked much interest within the scientific community because it promises a new era of cancer management. We here review its application in a subset of tumors characterized by the presence of the ALK oncogene: patients affected by these tumors can benefit from targeted therapy, but show frequent relapses, which call for improved methods of disease detection.
READ ARTICLE

Cancers DOI:10.3390/cancers13205149

Authors: Villa, Matteo, Geeta G. Sharma, Chiara Manfroni, Diego Cortinovis, and Luca Mologni

Review Paper, group2Kirk SmithOctober 14, 2021ALK, lung cancer, liquid biopsy

Brigatinib treated ALK positive lung squamous cell carcinoma after failed chemotherapy: A case report

The definitive efficacy of anaplastic lymphoma kinase (ALK) inhibitors in ALK positive lung squamous cell carcinoma (sqCC) patients remain unclear. Here, we report a case in which brigatinib had a therapeutic effect on ALK-positive lung squamous cell carcinoma. The patient in this report was diagnosed with ALK-positive lung squamous cell carcinoma with brain metastases, and received brigatinib after failure of first-line chemotherapy. Response duration was approximately 11 months, with tolerable side effects. In conclusion, a good clinical effect was achieved in a patient with ALK positive lung squamous cell carcinoma who received treatment with an ALK inhibitor. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14133

Authors: Shuluan Li, Pei Zhang, Tianyu Wang, Jie Wang, Jianchun Duan,

Case Study, group2Kirk SmithOctober 13, 2021ALK, brigatinib, chemotherapy lung squamous cell carcinoma

Structural basis of cytokine-mediated activation of ALK family receptors

Anaplastic lymphoma kinase (ALK)1 and the related leukocyte tyrosine kinase (LTK)2 are recently deorphanized receptor tyrosine kinases3. Together with their activating cytokines, ALKAL1 and ALKAL24,5,6 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development7, cancer7,8,9 and autoimmune diseases10. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain11, consistent with a metabolic role for Drosophila ALK12. Despite such functional pleiotropy and growing therapeutic relevance13,14, structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles..... READ ARTICLE

Nature DOI:10.1038/s41586-021-03959-5

Authors: Steven De Munck, Mathias Provost, Michiko Kurikawa, Ikuko Omori, Junko Mukohyama, Jan Felix, Yehudi Bloch, Omar Abdel-Wahab, J. Fernando Bazan, Akihide Yoshimi & Savvas N. Savvides

Pre-Clinical, group2Kirk SmithOctober 13, 2021cancer, metabolism, X-ray crystallography, ALK

A Novel ME1-ALK Fusion Identified in an Invasive Lung Adenocarcinoma Patient with Micropapillary and Solid Patterns: Case Report

Background: Anaplastic Lymphoma Kinase (ALK) re arrangement is observed in about 3% to
7% lung Adenocarcinoma (ADC). With the development of Next-Generation Sequencing (NGS)
technology, more novel ALK fusions have been discovered, which can provide patients more
opportunities to receive target therapies and achieve clinical effects.
Case Report: A case of an invasive lung ADC patient with micropapillary and solid patterns
harboring a novel ALK fusion (ME1-ALK) was reported. Then, thoracoscopic resection of right upper
lung and cautery division of pleural adhesions were performed with general anesthesia. Considering
that solid and micropapillary components accounted for 50%, nedaplatin plus pemetrexed were
administrated for 4 cycles after operation with the patient's consent. The patient had no recurrence
and the Disease Free Survival (DFS) was 10 months by May 17th, 2021.
Conclusion: This case highlights that NGS profiling can identify more novel fusions and help solid/
micropapillary-lung ADC patients find more opportunities to receive target therapies if the patient
recurrence. READ ARTICLE

Annuals of Clinical Case Report DOI:ISSN: 2474-1655

Authors: Wang X, Zhang C, Shang Z, Yang D, Li M, Luo N, Wu Y

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

Dr Ignatius Ou on ALKtALK

Dr. Ignatius Ou speaks to the ALK Positive community about how he came to study ALK. He gives a presentation about variants and describes his clinical practices. He educates the ALK community about everything from ALK trials to surgery for stage IV patients. WATCH VIDEO

ALK Positive Inc.

Authors: Dr. Ignatius Ou

Video, group2Kirk SmithOctober 10, 2021ALKtALK

Efficacy of Targeted Inhibitors in Metastatic Lung Squamous Cell Carcinoma With EGFR or ALK Alterations

The efficacy of targeted therapies in oncogene-driven lung adenocarcinomas (LUADs) has been well established; however, the benefit for EGFR-mutant or ALK-rearranged lung squamous cell carcinomas (LUSCs) is less known, partially owing to the rarity of the incidence. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtocrr.2021.100237

Authors: Whitney E. Lewis, Lingzhi Hong, Frank E. Mott, George Simon, Carol C. Wu, Waree Rinsurongkawong, J. Jack Lee, Vincent K. Lam, John V. Heymach, Jianjun Zhang, Xiuning Le

Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC

Gene fusion variants in ALK-rearranged NSCLC may predict patient outcomes, but previous results have been inconclusive. Fusion isoforms coexisting in the same tumor may affect the efficacy of targeted therapy, but they have not been investigated.
Patients with ALK-rearranged NSCLC who received crizotinib treatments were recruited. Precrizotinib tumor tissues were analyzed by the anchored multiplex polymerase chain reaction for targeted RNA sequencing. Kaplan-Meier and Cox regression were used to compare overall and progression-free survivals.
It was concluded that intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Zhengbo Song, Shifeng Lian, Silvia Mak, Maggie Zi-Ying Chow, Chunwei Xu, Wenxian Wang, Hoi Yee Keung, Chenyu Lu, Firaol Tamiru Kebede, Yanqiu Gao, Wah Cheuk, William Chi Shing Cho, Mengsu Yang, Zongli Zheng

Assessment of Alectinib vs Ceritinib in ALK-Positive Non–Small Cell Lung Cancer in Phase 2 Trials and in Real-world Data

How robust are conclusions about the comparative effectiveness of the ALK inhibitor alectinib vs ceritinib in crizotinib-refractory, ALK-positive non–small cell lung cancer from indirect comparisons using real-world data (RWD)? This comparative effectiveness study including 355 patients found that alectinib exposure was associated with improved survival compared with ceritinib in both single-group trials and multicenter US RWD. Results were robust to a range of plausible assumptions about unmeasured confounding and missing Eastern Cooperative Oncology Group Performance Status and underrecorded comorbidities in RWD. Alectinib exposure was associated with longer OS compared with ceritinib in patients with ALK-positive NSCLC, and only substantial levels of bias examined reversed the findings. These findings suggest that quantitative bias analysis can be a useful tool to address uncertainty of findings for decision-makers considering RWD. READ ARTICLE

JAMA Network Open DOI:10.1001/jamanetworkopen.2021.26306

Authors: Wilkinson S, Gupta A, Scheuer N, Mackay E, Arora P, Thorlund K, Wasiak R, Ray J, Ramagopalan S, Subbiah V.

Clinical Trials, group2Kirk SmithOctober 1, 2021Alectinib, Ceritinib, Non–Small Cell Lung Cancer, Trials

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

Successful treatment with lorlatinib in a patient with meningeal carcinomatosis of ALK-positive non-small cell lung cancer resistant to alectinib and brigatinib

Although anaplastic lymphoma kinase (ALK) inhibitors are effective treatment options for ALK-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis, achieving long-term survival in patients with NSCLC with meningeal carcinomatosis resistant to ALK inhibitors is difficult. Lorlatinib, a third-generation ALK inhibitor, was designed for selective CNS penetration, and exerts potent antitumor activity against tumors resistant to first- and/or second-generation ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis. Here, we report a case of ALK-positive lung adenocarcinoma with meningeal carcinomatosis in which lorlatinib was used after resistance to alectinib and brigatinib.We find lorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors. Therefore, lorlatinib should be considered in such cases, even when patients exhibit serious symptoms associated with meningeal carcinomatosis. READ ARTICLE

Medicine DOI:10.1097/MD.0000000000027385

Authors: Nakashima, Koki MD, Demura, Yoshiki MD, PhD, Kurokawa, Kosuke MD, Takeda, Toshihiro MD, Jikuya, Norihiro MD, Oi, Masahiro MD, Tada, Toshihiko MD, Akai, Masaya MD, PhD, Ishizuka, Tamotsu MD, PhD

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.713530

Authors: Yue Pan, Chao Deng, Zhenhua Qiu, Chenghui Cao and Fang Wu

Predictive role of neutropenia under crizotinib treatment in ALK-rearranged nonsmall cell lung cancer patients: A single-institution retrospective analysis

Anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Tyrosine kinase inhibitor crizotinib, an anticancer drug acting as an ALK inhibitor, has shown remarkable response in ALK-positive NSCLC. The aim of our study is to explore the adverse events (AEs) of patients on crizotinib therapy and analyze the predictability of AEs for better survival or response on NSCLC patients. We find that neutropenia under crizotinib treatment was found to be associated with improved PFS suggesting that neutropenia might be an important determinant in treatment and survival strategies. READ ARTICLE

Indian Journal of Cancer DOI:10.4103/ijc.IJC_71_20

Authors: Pınar Gürsoy, Burcu Çakar, Deniz Nart, Erdem Göker

Real-World OutcomesKirk SmithSeptember 30, 2021ALK, NSCLC, crizotinib, AE, neutropenia, PFS

Next-generation sequencing using liquid biopsy in the care of patients with ALK-rearranged non-small cell lung cancer: a focus on lorlatinib

Next-generation sequencing (NGS) has introduced new applications in the molecular profiling of lung cancer, expanding its use from the essential molecular diagnosis in advanced stages, to disease monitoring and the study of resistance mechanisms to targeted therapies and, most recently, to immunotherapy. Cell-free DNA (cfDNA) NGS is an easily accessible form of liquid biopsy, with the potential of sequencing tumor DNA shed from different metastasis and capturing tumor heterogeneity and tumor clonal evolution during treatment. Lorlatinib, is a novel third-generation ALK inhibitor, and current standard treatment for patients that experience disease progression with crizotinib and a second-generation ALK inhibitor or in the front line setting. Preclinical studies on predictive biomarkers of response and resistance to lorlatinib have been conducted, shedding a light on potential biological mechanisms of primary and acquired resistance to this compound. With the emerging role of cfDNA NGS, ..... READ ARTICLE

Precision Cancer Medicine (PCM) DOI:10.21037/pcm-20-59

Authors: Juan B. Blaquier, Andrés F. Cardona, Alessandro Russo, Christian Rolfo, Gonzalo Recondo

Kirk SmithSeptember 30, 2021

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.

Identification of a Novel SLC8A1-ALK Fusion and Non-Canonical Expression Significantly Responding to ALK-TKIs in Lung Adenocarcinoma: A Case Report

Approximately 2–7% of patients with non-small cell lung cancer harbor anaplastic lymphoma kinase (ALK) rearrangement events. Of note, typical ALK actionable rearrangements are sensitive to treatment with tyrosine kinase inhibitors (TKIs). However, different types of ALK fusion influence the clinical outcomes of this therapeutic approach. Approximately 10–40% of patients with ALK-fusion positive non-small cell lung cancer do not response to ALK-TKI therapy. Therefore, it is important to accurately identify the types of ALK rearrangement for appropriate selection of clinical treatment. We find a strategy combining DNA-targeted next-generation sequencing with RNA reverse transcriptase-polymerase chain reaction and sequencing, besides fluorescence in situ hybridization and immunohistochemistry, may provide an effective and practical solution for correct identification of partner genes and fusion structures in the diagnosis of ALK rearrangements, particularly for non-canonical expression patterns of ALK fusion events. The combined approach may lead to more benefits for patients. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S319845

Authors: Xingyu Zhu, Yuqi He, Yin Wang,Yan Lei, Xiaoxing Su, Yifan Liu, Shuangxiu Wu, Zhengfu He

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