P=N/A, N=20, Recruiting, Peking University Shenzhen Hospital

P=N/A, N=10, Not yet recruiting, Peking University Shenzhen Hospital; Peking University Shenzhen Hospital

P=N/A, N=200, Not yet recruiting, Shandong First Medical University and Shandong Academy of Medical Sciences (Shandong Cancer Hospital ＆Institute); Shandong First Medical University

P4, N=598, Recruiting, Jiangsu Cancer Hospital; Jiangsu Cancer Hospital

P4, N=178, Not yet recruiting, Beijing chest hospital capital medical university; Beijing Chest Hospital Capital Medical University

P4, N=20, Not yet recruiting, The Second Affiliated Hospital of Air Force Medical University; The Second Affiliated Hospital of Air Force Medical University

P2, N=45, Not yet recruiting, Shanghai Pulmonary Hospital; Shanghai Pulmonary Hospital

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.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, remains a major therapeutic challenge in EGFR-mutant lung cancer...These effects were enhanced when combined with brigatinib, a clinically approved multi-kinase inhibitor with activity against mutant EGFR...Collectively, these findings suggest that magnolol exerts multitargeted effects involving inhibition of mutant EGFR, suppression of the AXL-cMyc signaling axis, and disruption of DNA repair, thereby sensitizing resistant tumors to EGFR-TKIs. Magnolol may represent a promising adjuvant strategy for overcoming acquired resistance in EGFR-mutant lung cancer.

Here, we report a case of an ALK-positive lung adenocarcinoma patient who developed resistance following sequential treatment with the ALK-TKI alectinib and lorlatinib, accompanied by histological transformation to LCNEC and concurrent genetic alterations including TP53 deletion, CDKN2A deletion, and MYC amplification. This case expands the spectrum of ALK-TKI resistance mechanisms and highlights the potential value of exploring combinatorial approaches incorporating immunotherapy, antiangiogenic therapy, and chemotherapy for the management of such cases.