Review
Pharmacology & Pharmacy
Annette K. Brenner, Maria W. Gunnes
Summary: Neuroblastoma is a malignant tumor that mostly affects young children and is highly heterogeneous, with risk factors including abnormalities in the ALK gene leading to tumorigenesis. Combination therapy with ALK inhibitors may be an effective strategy to reduce drug resistance and improve treatment outcomes.
Review
Oncology
Yuan Wang, Jing He, Manyu Xu, Qingfeng Xue, Cindy Zhu, Juan Liu, Yaping Zhang, Wenyu Shi
Summary: This review provides an overview of research progress on ALK+ ALCL, including the study of drug resistance mechanisms and the application and development of new therapies. Potential treatment strategies are proposed to guide the design of future clinical trials.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Giulia Arosio, Geeta G. Sharma, Matteo Villa, Mario Mauri, Ilaria Crespiatico, Diletta Fontana, Chiara Manfroni, Cristina Mastini, Marina Zappa, Vera Magistroni, Monica Ceccon, Sara Redaelli, Luca Massimino, Anna Garbin, Federica Lovisa, Lara Mussolin, Rocco Piazza, Carlo Gambacorti-Passerini, Luca Mologni
Summary: Combining two drugs for the treatment of ALK+ ALCL can effectively prevent the emergence of resistant cells, showing superior efficacy compared to single drug treatments in controlling the expansion of lymphoma cells in the long term.
Article
Oncology
Giulia Mura, Elif Karaca Atabay, Matteo Menotti, Cinzia Martinengo, Chiara Ambrogio, Gloria Giacomello, Maddalena Arigoni, Martina Olivero, Raffaele A. Calogero, Roberto Chiarle, Claudia Voena
Summary: Anaplastic Large Cell Lymphoma (ALCL) is driven by the chimeric tyrosine kinase NPM-ALK, which downregulates the expression of CD45 via STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment. CD45 is a key regulator of T cell activation and cytokine responses through the JAK/STAT pathway. In ALK+ ALCL, NPM-ALK inhibits T cell molecules expression and activates surrogate TCR signaling. Inhibition of NPM-ALK kinase activity leads to increased expression of CD45RO isoform. Knocking-out CD45 results in increased resistance to ALK TKI treatment.
FRONTIERS IN ONCOLOGY
(2023)
Article
Hematology
Elif Karaca Atabay, Carmen Mecca, Qi Wang, Chiara Ambrogio, Ines Mota, Nina Prokoph, Giulia Mura, Cinzia Martinengo, Enrico Patrucco, Giulia Leonardi, Jessica Hossa, Achille Pich, Luca Mologni, Carlo Gambacorti-Passerini, Laurence Brugieres, Birgit Geoerger, Suzanne D. Turner, Claudia Voena, Taek-Chin Cheong, Roberto Chiarle
Summary: This study identified PTPN1 and PTPN2 phosphatases as drivers of resistance to ALK TKIs in ALK(+) ALCL. These phosphatases regulate ALK phosphorylation and activity, and their loss leads to TKI resistance. Furthermore, SHP2 is a key mediator of oncogenic ALK signaling, and PTPN1 acts as a phosphatase for SHP2. Combination therapy with a SHP2 inhibitor can overcome TKI resistance in ALK(+) ALCL.
Article
Cell Biology
Shuai Liang, Qing Wang, Xuesen Qi, Yudi Liu, Guozhen Li, Shaoyong Lu, Linkai Mou, Xiangyu Chen
Summary: The double mutations I1171N/F1174I in the ALK kinase domain reduced the conformational dynamics and significantly disturbed the conserved hydrogen bonding interactions from the hinge residues in the lorlatinib-bound state, while they had little impact on the gilteritinib-bound state. This discrepancy enabled the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib in non-small cell lung cancer.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Oncology
Elissa Andraos, Josephine Dignac, Fabienne Meggetto
Summary: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase associated with Anaplastic Large Cell Lymphoma (ALCL) through oncogenic translocations, mainly NPM-ALK. Chemotherapy is effective in ALK(+) ALCL patients and induces remission rates of approximately 80%, but some patients do not respond and have relapses. Different classes of ALK tyrosine kinase inhibitors are available, primarily used for EML4-ALK (+) lung cancers.
Article
Chemistry, Medicinal
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, Shengtao Xu
Summary: Novel ALK degraders based on PROTAC technology showed high specificity in ALK-positive cell lines and significant anti-tumor effects in a mouse model, indicating potential benefits for treating ALK-driven malignancies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
V. Subbiahy, S. Kuraviy, 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, R. Balusu
Summary: The study demonstrates that Ceritinib shows inhibitory effects on the fusion kinase NPM1-ALK and induces apoptosis of lymphoma cells in vitro and in vivo. Treatment with Ceritinib in the NPM1-ALKthorn ALCL xenograft model resulted in tumor regression and improved survival. Among 19,272 patients sequenced, 0.30% harbored ALK fusions, including various hematologic malignancies.
Review
Medicine, General & Internal
Kuan-Li Wu, Hsiao-Ling Chen, Ying-Ming Tsai, Tai-Huang Lee, Hsiu-Mei Chang, Yu-Chen Tsai, Cheng-Hao Chuang, Yong-Chieh Chang, Yu-Kang Tu, Chih-Jen Yang, Jen-Yu Hung, Inn-Wen Chong
Summary: This study compared newer generation ALKIs for treatment efficacy in Asian groups using network meta-analysis. Results showed that ensartinib may currently be the most effective first-line treatment for Asian patients with ALK-positive NSCLC. Additionally, low-dose alectinib exhibited efficacy similar to a higher dose regimen in Asian populations.
JOURNAL OF CLINICAL MEDICINE
(2021)
Review
Oncology
Li Wang, Wen Wang
Summary: ALK-TKIs have shown excellent clinical efficacy in treating ALK-positive NSCLC as first-line therapy, but resistance and adverse effects remain challenges. Proper management of these adverse effects is crucial in improving patient quality of life.
Article
Multidisciplinary Sciences
Yoko Ota, Hiroyuki Yoda, Takahiro Inoue, Takayoshi Watanabe, Yoshinao Shinozaki, Atsushi Takatori, Hiroki Nagase
Summary: The study demonstrates the inhibitory effects of the newly developed ALK inhibitor CCC-003 on cell proliferation in ALK-mutated neuroblastoma, suggesting its potential for treating neuroblastoma and overcoming tyrosine kinase inhibitor resistance. CCC-003 preferentially binds to mutated DNA within the ALK gene and exerts anti-tumor activity through a distinct mode of action compared to other ALK inhibitors.
Review
Chemistry, Medicinal
Deyi Ma, Mengrao Guo, Xin Zhai
Summary: This paper provides a comprehensive review of the patent literature from 2018 to 2022 regarding small molecular ALK inhibitors, including their structures, pharmacological data, and utilization as anticancer agents. It also describes several potential ALK inhibitors on the market or under clinical investigations in detail.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2023)
Article
Pathology
Jung-Woo Choi, Youngseok Lee, Hyunchul Kim, Hyun Yee Cho, Soo Kee Min, Young-Sik Kim
Summary: In solid tumors and malignant lymphomas, lactate transport is regulated by different monocarboxylate transporters. Malignant lymphomas with ALK(+) ALCL show a unique metabolic phenotype characterized by high coexpression of MCT1 and MCT4 in tumor cells. Immunostaining for MCT4, together with ALK, can be useful for the differential diagnosis of ALK(-) ALCL and peripheral T-cell lymphoma. Dual targeting of MCT1 and MCT4 may be an appropriate therapeutic approach for ALK(+) ALCL.
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
(2022)
Review
Pharmacology & Pharmacy
Kajetan Kielbowski, Justyna Zychowska, Rafal Becht
Summary: This review summarizes the efficacy and safety profile of ALK inhibitors, describes off-target anticancer effects, and discusses resistance mechanisms in the context of personalized oncology.
FRONTIERS IN PHARMACOLOGY
(2023)