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

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

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