Alk-KO Mouse

Alk, short for anaplastic lymphoma kinase, is a receptor tyrosine kinase. It plays a significant role in various biological processes and is involved in multiple signaling pathways relevant to cell growth, differentiation, and survival [3]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable tools for studying its functions.

Alk gene alterations, including point mutations, deletions, and rearrangements, are associated with numerous malignancies. In non-small cell lung cancer (NSCLC), the EML4-Alk fusion is prevalent, accounting for about 85% of all fusion variants in Alk-positive NSCLC [3,6]. Different Alk fusion proteins can lead to distinct signaling outputs. Alk inhibitors have been developed to target these alterations. First-generation inhibitor crizotinib and subsequent generations like ceritinib, alectinib, brigatinib, ensartinib, and the third-generation lorlatinib have improved progression-free survival in Alk-positive NSCLC patients [1]. However, resistance to these inhibitors often occurs, either as on-target or off-target alterations [1,4,5]. In neuroblastoma, Alk is an oncogenic driver, and Alk inhibitors can upregulate Alk expression, enhancing the efficacy of Alk.CAR-T cells [2].

In conclusion, Alk is crucial in cancer biology, especially in NSCLC and neuroblastoma. Studies using KO or CKO mouse models (not specifically detailed in provided references but generally valuable) could potentially further elucidate its role in disease development. The development of Alk inhibitors has improved patient outcomes, but understanding resistance mechanisms remains a key area of research to optimize treatment strategies for Alk-positive diseases [1-5].

References:

1. Peng, Ling, Zhu, Liping, Sun, Yilan, Zhang, Yongchang, Yu, Zhentao. 2022. Targeting ALK Rearrangements in NSCLC: Current State of the Art. In Frontiers in oncology, 12, 863461. doi:10.3389/fonc.2022.863461. https://pubmed.ncbi.nlm.nih.gov/35463328/

2. 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/

3. 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/

4. 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/

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. 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/