![]() Other mechanisms of resistance are amplification of ALK fusion gene, alone or in combination with other molecular alterations ( 6), or bypass pathways such as amplification of epidermal growth factor receptor (EGFR) or of insulin-like growth factor (IGF-1R) or cKIT mutation ( 12- 14).Īmong 60–90% of patients receiving crizotinib has a CNS progression which is the first site of relapse in 46% of cases without evidence of extracranial worsening ( 3, 15- 17). These alterations increase the affinity for adenosine triphosphate, inducing conformational changes with steric hindrance and interference with the downstream signaling pathway ( 6- 11). Despite these results, after a median period of 10.9 months all patients progress due to the development, in approximately one third of patients, of acquired resistance mutations in the ALK tyrosine kinase domain, such as L1196M, G1269A, C1156Y, L1152R, G1202R, S1206Y, 1151Tins, F1174C, and D1203N. Crizotinib, a I generation multi-TKI, initially developed as a mesenchymal-epithelial transition factor (MET) inhibitor, was the first used in clinic due to results of PROFILE trials showing median progression-free survival (mPFS), objective response rate (ORR) and median duration of response (mDOR) higher than those of chemotherapy in all lines of treatment ( 4, 5). In this setting, the main therapeutic strategy is represented by anti-ALK rearrangement tyrosine kinase inhibitors (TKIs). In approximately 30% of these patients central nervous system (CNS) involvement is present at diagnosis ( 3). Patients affected by this tumor are frequently young, women, with a limited or absent history of smoking and often with a histologic diagnosis of a signet-ring cell adenocarcinoma ( 2). Accepted for publication Sep 18, 2019.Īnaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations, present in 3–7% of non-squamous non-small cell lung cancers (NSCLC) ( 1). Keywords: Anti-anaplastic lymphoma kinase tyrosine kinase inhibitors (anti-ALK TKIs) resistance alectinib ceritinib brigatinib In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting. ![]() Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. ![]() This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. Moreover, 60–90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. ![]() The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Policy of Dealing with Allegations of Research MisconductĪbstract: Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3–7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features.Policy of Screening for Plagiarism Process. ![]()
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