Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for Ceritinib

Abstract

The fusion of echinoderm microtubule-associated protein-like 4 with the anaplastic lymphoma kinase (EML4-ALK) is found in 3%–7% of non-small-cell lung cancer (NSCLC) cases and confers sensitivity to crizotinib, the first United States Food and Drug Administration (FDA)-approved ALK inhibitor drug. Although crizotinib has an excellent initial therapeutic effect, acquired resistance to this drug invariably develops within the first year of treatment. Resistance may involve secondary gatekeeper mutations within the ALK gene interfering with crizotinib–ALK interactions, or compensatory activation of aberrant bypass signaling pathways. New therapeutic strategies to overcome crizotinib resistance are needed. Ceritinib, a second-generation ALK inhibitor, overcomes several crizotinib-resistant ALK mutations and has demonstrated efficacy against tumor growth in several in vitro and in vivo preclinical models of crizotinib resistance. Notably, the dose-escalation Phase I ASCEND-1 trial has shown a marked activity of ceritinib in both crizotinib-naïve and crizotinib-resistant ALK-rearranged lung cancer. The overall response rate was 58% in a subgroup of patients with ALK-rearranged late-stage NSCLC. Drug discontinuation rate due to toxicity was 10%. The standard dose was established at 750 mg daily. This paper outlines the pathogenesis and treatment of ALK-positive lung cancer, focuses on the preclinical and clinical results surrounding the accelerated FDA approval of ceritinib for the treatment of ALK-positive metastatic NSCLC patients who have progressed on/or are crizotinib intolerant, and discusses the potential efforts seeking to maximize ceritinib efficacy and expand its usage to other indications in cancer therapy.

Identification of EML4-ALK as an alternative fusion gene in epithelioid inflammatory myofibroblastic sarcoma

“…EML4-ALK fusion genes have attracted great attention from oncologists focusing on lung cancer since two related landmark studies were published. Though harbored by only 4–6% of lung adenocarcinomas, EML4-ALK fusion has been recognized as the second most important event to consider in the targeted treatment of lung cancer, following the EGFR mutation [ 25 , 26 ]. According to data derived from studies of lung cancer, EML4-ALK fusion occurs through a paracentric inversion within the short arm of chromosome 2, where EML4 and ALK genes are both located.…”

Active fraction (HS7) from Taiwanofungus camphoratus inhibits AKT-mTOR, ERK and STAT3 pathways and induces CDK inhibitors in CL1-0 human lung cancer cells

“…The signal transducer and activator of transcription 3 (STAT3) is one of the three major downstream pathways (AKT-mTOR, ERK and STAT3) activated by EGFR phosphorylation, which promote proliferation and survival of NSCLC cells [ 9 , 26 ]. Constitutive activation of STAT3 is also a common feature in NSCLC and it can be activated by JAK2 independent of known driver mutations [ 27 ].…”

Panomics for Precision Medicine

“…(although drug resistance and tumor recurrence remain important concerns) 1011 . Other prominent targeted therapies include the use of HER2/neu blockage in breast cancers with Herceptin 12 , lymphoma kinase (ALK) inhibitors such as Crizotinib in lung cancer 13 , and EGFR receptor antagonists in lung and colon cancers, such as Gefitinib 14 . Despite this type of targeted approach, there are still some patients that do not respond to therapy or who present only a partial response even though the targeted mutation is present 15 .…”