Mechanisms of Clinical Resistance to Small Molecule Tyrosine Kinase Inhibitors Targeting Oncogenic Tyrosine Kinases
A number of highly specific small molecule inhibitors of oncogenic tyrosine kinases have been developed and may potentially improve the treatment of different malignant diseases. However, it became rapidly evident that multiple resistance mechanisms compromise the successful clinical application of these inhibitors, particularly in advanced solid tumors. To develop efficient therapeutic strategies with small molecule inhibitors, one must understand the causes for treatment failure. Three different types of resistance to small molecule inhibitors of oncogenic tyrosine kinases have been observed. The malignant phenotype may be independent of the activity of the target kinase (target-independent resistance). Alternatively, overexpression or mutation of the target kinase can counteract the inhibition of oncogenic tyrosine kinases (target-dependent resistance). Finally, alterations of drug transporters or drug-metabolizing pathways may block the bioavailability of the tyrosine kinase inhibitors (drug-dependent resistance). This article reviews the current knowledge of clinical resistance to small molecule inhibitors approved for treatment of cancer patients.
Available from: Wei-Xiang Qi
- "Indeed, synergistic antitumor activity achieved by combining targeted agents has been observed in preclinical and clinical studies , , , . Furthermore, introducing combination therapy early in the course of a disease could prevent the emergence of drug resistance , , , . As a result, several trials have been conducted in recent years to determine the clinical benefits gained from a number of combined inhibition strategies in this setting, but most of these trials are characterized by a small sample size, with inadequately statistical power to exclude clinically relevant differences in efficacy. "
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ABSTRACT: Combining targeted therapy has been extensively investigated in previously treated advanced non-small-cell lung cancer (NSCLC), but it is still unclear whether combining targeted therapy might offer any benefits against standard monotherapy with erlotinib. We thus performed a meta-analysis of randomized controlled trials to compare the efficacy and safety of combining targeted therapy versus erlotinib alone as second-line treatment for advanced NSCLC.
Several databases were searched, including Pubmed, Embase and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3 or 4 adverse event (AEs). The pooled hazard ratio (HR) or odds ratio (OR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.
Eight eligible trials involved 2417 patients were ultimately identified. The intention to treatment (ITT) analysis demonstrated that combining targeted therapy significantly improved OS (HR 0.90, 95%CI: 0.82-0.99, p = 0.024), PFS (HR 0.83, 95%CI: 0.72-0.97, p = 0.018), and ORR (OR 1.35, 95%CI 1.01-1.80, P = 0.04). Sub-group analysis based on phases of trials, EGFR-status and KRAS status also showed that there was a tendency to improve PFS and OS in combining targeted therapy, except that PFS for patients with EGFR-mutation or wild type KRAS favored erlotinib monotherapy. Additionally, more incidence of grade 3 or 4 rash, fatigue and hypertension were observed in combining targeted therapy.
With the available evidence, combining targeted therapy seems superior over erlotinib monotherapy as second-line treatment for advanced NSCLC. More studies are still needed to identify patients who will most likely benefit from the appropriate combining targeted therapy.
PLoS ONE 02/2013; 8(2):e55637. DOI:10.1371/journal.pone.0055637 · 3.23 Impact Factor
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ABSTRACT: Inhibition of oncogenic protein kinases by small compound inhibitors has proven to be a valuable strategy for the directed and target-specific treatment of an ever-increasing number of cancer types. These include the treatment of chronic myeloid leukemia with the Bcr-Abl inhibitor imatinib and non-small-cell lung cancer with the epidermal growth factor inhibitors erlotinib and gefitinib. Unfortunately, initially successful therapy is often hampered by relatively rapid onset of resistance to the drug and subsequent relapse, particularly in patients with advanced disease. In the majority of cases this is caused by expansion of clones containing mutated forms of the targeted kinases, which confer insensitivity to the drug of the cancer cell. In addition, multiple factors including pharmacokinetic issues such as suboptimal drug delivery further contribute to resistance formation. Loss of target dependence due to the activation of parallel signaling pathways has also been reported as cause for acquired drug insensitivity. Here, we discuss currently applied as well as potential future strategies that can be applied to overcome and avoid resistance to drug therapy.
Drugs in R & D 02/2006; 7(2):73-86. DOI:10.2165/00126839-200607020-00002 · 1.71 Impact Factor
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ABSTRACT: Acute myeloid leukaemia (AML) comprises 80% of acute adult leukaemias and the disease has mostly an unfavourable outcome. Diagnostic criteria rely primarily on morphological classification, while prognostic evaluation is determined by cytogenetic methods. Survival is highly variable and it is a matter of debate, whether alternative therapeutic approaches may improve the effectiveness of conventional cytotoxic drug treatment. Two transmembrane proteins undoubtedly contribute to worse prognosis: P-glycoprotein (Pgp) and FLT3. Pgp is a transmembrane, ATP-cassette binding efflux pump that efficiently removes structurally unrelated xenobiotics from leukaemic blasts. This leads to inefficiency towards several cytotoxic drugs, hence the phenomenon is called multidrug resistance. FLT3 is a transmembrane tyrosine kinase and an internal tandem duplication can considerably augment its kinase activity. Both mechanisms lead to chemotherapy resistance and significantly shorter survival; thus several studies have been designed to treat patients via therapeutic measures that neutralize these proteins. This review focuses on the pathophysiological phenomena and the detection methods of Pgp and FLT3 as well as on novel therapeutic strategies that are offered by their inhibition.
Current Medicinal Chemistry 02/2007; 14(5):519-30. DOI:10.2174/092986707780059661 · 3.85 Impact Factor
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