Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase. It plays a crucial role in various biological processes, and its abnormal activation can lead to oncogenesis. Different ALK gene alterations, such as point mutations, deletions, and rearrangements, have been identified across a range of tumour types [2]. These alterations can disrupt normal cellular signalling pathways, making ALK an important target for cancer research [2].

ALK rearrangements are oncogenic drivers in several malignancies, most notably in 3-7% of advanced non-small cell lung cancer (NSCLC) [3,5]. In NSCLC, the EML4-ALK fusion is the most prevalent, with different EML4-ALK variants showing differential responses to ALK tyrosine kinase inhibitors (TKIs) [2,7]. In neuroblastoma, ALK is an oncogenic driver, and ALK inhibitors can increase ALK expression, sensitizing cells to ALK.CAR-T cells [1]. Resistance to ALK inhibitors, both on-target and off-target, is a significant issue. For example, different ALK inhibitors are associated with distinct spectra of ALK resistance mutations, and sequential use of inhibitors can lead to the emergence of compound ALK mutations that confer resistance to drugs like lorlatinib [4,6].

In conclusion, ALK is a key molecule in cancer biology, especially in NSCLC and neuroblastoma. Research on ALK, including studies using genetic models (although not specifically KO/CKO mouse models in the provided references), has led to the development of ALK-targeted drugs. Understanding ALK's role in tumour biology and resistance mechanisms to its inhibitors is crucial for optimizing therapeutic strategies for ALK-positive diseases.

References:

1. Bergaggio, Elisa, Tai, Wei-Tien, Aroldi, Andrea, Dotti, Gianpietro, Chiarle, Roberto. 2023. ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells. In Cancer cell, 41, 2100-2116.e10. doi:10.1016/j.ccell.2023.11.004. https://pubmed.ncbi.nlm.nih.gov/38039964/

2. Hallberg, B, Palmer, R H. . The role of the ALK receptor in cancer biology. In Annals of oncology : official journal of the European Society for Medical Oncology, 27 Suppl 3, iii4-iii15. doi:10.1093/annonc/mdw301. https://pubmed.ncbi.nlm.nih.gov/27573755/

3. Poei, Darin, Ali, Sana, Ye, Shirley, Hsu, Robert. 2024. ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies. In Cancer drug resistance (Alhambra, Calif.), 7, 20. doi:10.20517/cdr.2024.25. https://pubmed.ncbi.nlm.nih.gov/38835344/

4. Gainor, Justin F, Dardaei, Leila, Yoda, Satoshi, Engelman, Jeffrey A, Shaw, Alice T. 2016. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. In Cancer discovery, 6, 1118-1133. doi:. https://pubmed.ncbi.nlm.nih.gov/27432227/

5. Desai, Aakash, Lovly, Christine M. 2023. Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review. In Translational lung cancer research, 12, 615-628. doi:10.21037/tlcr-22-708. https://pubmed.ncbi.nlm.nih.gov/37057106/

6. Yoda, Satoshi, Lin, Jessica J, Lawrence, Michael S, Hata, Aaron N, Shaw, Alice T. 2018. Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. In Cancer discovery, 8, 714-729. doi:10.1158/2159-8290.CD-17-1256. https://pubmed.ncbi.nlm.nih.gov/29650534/

7. Zhang, Shannon S, Nagasaka, Misako, Zhu, Viola W, Ou, Sai-Hong Ignatius. 2021. Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC. In Lung cancer (Amsterdam, Netherlands), 158, 126-136. doi:10.1016/j.lungcan.2021.06.012. https://pubmed.ncbi.nlm.nih.gov/34175504/