EML4 (EMAP Like 4)

The patient with TRIM24::ALK fusion, following durable responses to alectinib and lorlatinib, relapsed with detection of on-target ALK kinase domain mutations (F1174V, I1171N) and MYC amplification on progression. Comprehensive molecular workup, including RNA-based NGS, is essential for detecting rare but actionable ALK rearrangements and optimizing therapeutic strategy. NGS of CSF was a valuable tool for the detection of clinically suspected leptomeningeal disease and disease monitoring.

This case highlights the value of next-generation sequencing-based profiling in detecting rare actionable alterations missed by standard tests. We also include a discussion on why the EML4-AKL fusion was not detected in the usual test.

After 3 months, targeted lesions regressed significantly, and progression-free survival exceeded 24 months with ongoing response. This demonstrates efficacy of the ALK inhibitor ceritinib in ALK-rearranged SMARCA4-dNSCLC and underscores the clinical value of genomic-guided therapy.

The patient received first-line osimertinib combined with pemetrexed/cisplatin, achieving durable disease control for 17 months...Treatment was switched to alectinib, leading to significant tumor regression and partial response. This case illustrates that in triple-positive NSCLC, initial EGFR-TKI combined with chemotherapy can achieve long-term control, while dynamic molecular profiling at progression is essential for identifying resistance mechanisms. Sequential targeted therapy guided by NGS remains a cornerstone for precision management in this complex molecular subtype.

This case demonstrates an exceptionally durable response to first-line alectinib in an ALK-positive LUAD patient with a concurrent rare RET variant. It underscores the long-term efficacy and tolerability of alectinib and highlights the importance of comprehensive genomic profiling in guiding personalized targeted therapy for genetically complex NSCLC.

Since the approval of crizotinib, several next-generation ALK inhibitors have been introduced, offering improved treatment outcomes. The phase III eXalt3 study, a global randomized open-label trial, compared the efficacy of ensartinib, a second-generation ALK inhibitor, with crizotinib in patients with advanced ALK-rearranged NSCLC who had not received prior ALK-targeted therapy. With superior systemic and intracranial efficacy, ensartinib stands as a promising option in precision oncology. Ongoing research into improved ALK inhibitors and novel therapeutic strategies, including immune-based approaches, is expected to further improve patient outcomes.

However, notably, certain mutations were exclusive to specific groups, such as B-Raf proto-oncogene, serine/threonine kinase (BRAF), anaplastic lymphoma kinase/echinoderm microtubule-associated protein-like 4 (ALK/EML4), and paired box 8 - peroxisome proliferator activator receptor gamma (PAX8-PPARG) in OPTCs or EIF1AX in OCs. Importantly, only 3.6% (1/28) of malignant OPTC/ONs were tested negative on molecular analysis, suggesting that ONs with negative molecular test results are more likely to be benign than malignant.

From first-generation Crizotinib to third-generation Lorlatinib, successive agents have been refined for target selectivity, central nervous system penetration, and coverage of resistance-associated mutations, substantially improving patient survival and intracranial disease control. Nonetheless, the emergence of acquired resistance remains an overarching challenge, mediated by secondary kinase domain mutations, activation of bypass signaling pathways, and tumor phenotypic transformation. This review presents an integrative synthesis of ALK-targeted therapeutic developments, elucidates underlying resistance mechanisms, and surveys emerging strategies, providing a comprehensive perspective on current advances and future directions in precision management of ALK-driven malignancies.

In vitro modeling demonstrated that EML4::NTRK3 confers imatinib resistance, while sensitizing GIST cells to NTRK inhibitors. This first reported instance of an NTRK fusion as a secondary event in GIST progression underscores the importance of testing for NTRK alterations in tumors that have developed resistance to tyrosine kinase inhibitors to ensure patients are offered all available therapeutic options.

Notably, ALK inhibitors compact the IDR subdomain and reduce oligomerization, whereas this effect is abolished by the resistance mutation ALKG1202R, suggesting that ALK inhibitors not only inhibit kinase activity but also modulate IDR dynamics. Our study reveals a structural basis linking IDR dynamics to variant-specific oligomerization in EML4-ALK, offering further insights into the regulation of oncogenic signaling and the development of targeted therapies.

The study established a novel diagnostic model for GC based on DN T cell signature genes, which shows robust predictive performance and significant clinical benefit. The findings underscore the important role of DN T cells and model genes in GC, providing new insights into early diagnosis and potential therapeutic targets for effective management of GC.

This inducible cancer model in naked mole rats offers a unique platform for uncovering mechanisms of cancer resistance and modeling rare pleomorphic lung carcinomas. See related article by Shepard et al., p. 35.