Abnormalities observed in ALK+-NSCLCs are mainly the result of gene rearrangement. Inversions in the p-arm of chromosome 2 lead to the conjunction of the echinoderm microtubule-associated protein-like 4 (EML4) and ALK genes, producing an active fusion protein that is detected in numerous carcinomas. Translocations of the ALK gene have been discovered in numerous carcinomas, including neuroblastomas, anaplastic lymphomas, and inflammatory myofibroblastic tumors,4 but the first instance of EML4–ALK translocation was described in 2007 using tumor cell samples from a 62-year-old NSCLC patient, in which the fusion gene induced the activation of the intracellular kinase domain of ALK.12 Meta-analyses reveal that the EML4–ALK fusion gene is correlated with younger, nonsmoking female populations.12–14 All EML4–ALK fusion genes observed in NSCLCs contain exons 20–29 of ALK (encoding the intracellular domain) and eight different EML4 exons, all of which activate the downstream signals of Ras/ERK1/2 and JAK/STAT.15,16 It has been suggested that the prevalence of both the ALK mRNA and protein (specifically, the intracellular kinase domain) in NSCLC patients is the product of the EML4–ALK translocation and not the intact ALK gene, which is consistent with the view that active EML4–ALK is an oncogenic driver for the growth of tumors in patients harboring thisALK translocation.17 The EML4–ALK fusion protein undergoes auto-phosphorylation of its intracellular ALK kinase domain, constitutively activating the Ras signaling pathway that ultimately results in uncontrolled cell growth.4

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First-generation ALK inhibitor: profile of crizotinib

Because the ALK kinase is required for oncogenic activity in this subdivision of NSCLCs, tyrosine kinase inhibitors (TKIs) have been developed as antitumor therapies. Crizotinib (formerly known as PF-02341066 and marketed as Xalkori®, Pfizer), while originally synthesized as a c-MET inhibitor, demonstrated remarkable antitumor activity in patients harboring ALK+ tumors.18,19 As a TKI, crizotinib acts to competitively inhibit the ATP-binding domain of ALK, effectively preventing its downstream mechanisms of proliferation/replication while simultaneously inducing apoptosis.20 An initial phase I clinical trial investigating crizotinib resulted in a response rate of 57% and a 6-month progression free survival (PFS) rate of 72% with only mild toxicities.21 These clinical results were deemed more favorable than response rates observed in NSCLC patients treated solely with platinum-based chemotherapies. The Food and Drug Administration approved crizotinib for the treatment ofALK+-NSCLC in August 2011. A recently published PROFILE 1014 Phase III trial compared the efficacy and safety profile of crizotinib vs chemotherapy (pemetrexed-cisplatin or pemetrexed-carboplatin) in previously untreated patients with advanced ALK+-NSCLC, and found that the crizotinib arm showed both improved PFS and overall response rate (ORR) (10.9 months and 74%, respectively) over the standard chemotherapy arm (7.0 months and 45%, respectively).22 Patients receiving crizotinib also self-reported more improvements in cancer-related pain and a better quality of life than patients receiving standard chemotherapy.22 Thus, crizotinib has become the standard of care in patients harboring ALK+ tumors.

Despite its initial success in the treatment of ALK+-NSCLC, resistance to crizotinib develops in patients after approximately 10 months of treatment.23 Numerous factors likely contribute to the development of crizotinib resistance. Missense mutations in the kinase domain of the fusion protein that result in either diminished crizotinib binding or increased ATP binding is one such potential mechanism of resistance.24 Currently, seven distinct acquired resistance mutations have been identified in crizotinib-resistant tumors: the two most common being the gatekeeper mutations L1196M and G1269A and the remaining five mutations L1171T, L1152R, C1156Y, G1202R, and S1206Y. Multiple, nonoverlapping resistance mutations of the ALK kinase domain have been observed in some patients.25 Others expressed mechanisms that activated downstream signaling pathways of ALK without mutating the kinase itself,26 and a small number of patients simply failed to respond to crizotinib in the absence of any resistance mutations.19 In vitro analysis also demonstrates that the multiple variants of the EML4–ALK fusion protein may exhibit variable sensitivities to TKIs, consistent with the clinical range of responses to crizotinib treatment.27 Therefore, while some secondary mutations may exhibit continued responses to crizotinib, other mutations may confer resistance to the TKI and ultimately lead to the progression of metastatic ALK+ tumors.

While crizotinib demonstrates substantial antitumor activity in systemic disease, it appears to be less efficacious in targeting CNS metastasis. This could be due to the fact that crizotinib has a poor ability to penetrate the blood–brain barrier. A case report of a 29-year-old patient with ALK+-NSCLC demonstrated cerebrospinal crizotinib concentration of only 0.616 ng/mL, compared to its systemic serum concentration of 237 ng/mL.28 This patient exhibited adequate control of his intrathoracic disease when he developed new progressive disease in his brain.28 Other possible explanations concerning the discrepancy between systemic and CNS crizotinib efficacy, including the development of genetically distinct tumors in the brain that are unaffected by crizotinib and induced secondary mutations in the ALK kinase domain within brain parenchyma that confer resistance to TKIs such as crizotinib, have been suggested.29 With an approximate rate of CNS metastases in NSCLC patients at 30%,30 a novel and improved method for delivering antitumor agents through the blood–brain barrier into the cerebrospinal fluid is of importance for tumor suppression in ALK+-NSCLC patients.