Tyrosine Kinase Inhibitors In Cancer Research Articles

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Cancer: Current Use and Future Prospects.

Tyrosine kinase inhibitors (TKIs) have emerged as a leading targeted cancer therapy, reducing the side effects often seen with non-targeted treatments, especially the damage to healthy cells. To tackle resistance, typically caused by epidermal growth factor receptor (EGFR) mutations, four generations of TKIs have been developed. Each generation has shown improved effectiveness and fewer side effects, resulting in better patient outcomes. For example, patients on gefitinib, a first-generation TKI, experienced a progression-free survival (PFS) of 10 months compared to 5 months with conventional chemotherapy. Second-generation TKI afatinib outperformed erlotinib and extended PFS to 11.1 months compared to 6.9 months with cisplatin. Third-generation TKIs further increased survival to 38.6 months, compared to 31.8 months with first-generation TKIs. This progress demonstrates the ability of newer TKIs to overcome resistance, particularly the T790M mutation, while reducing adverse effects. Ongoing research focuses on overcoming resistance from newer mutations like C797S to further improve patient survival. These developments highlight the significant progress in TKI therapy and the continued effort to refine cancer treatment. Recent research in South Korea shows that third-generation TKIs are ineffective against non-small cell lung cancer (NSCLC) with the C797S mutation. Several trials have started showing promising in vitro and in vivo results, but more trials are needed before clinical approval. This review underscores notable advancements in the field of EGFR TKIs, offering a comprehensive analysis of their mechanisms of action and the progression of various TKI generations in response to resistance.

Receptor tyrosine kinase inhibitors in cancer.

Targeted therapy is a new cancer treatment approach, involving drugs that particularly target specific proteins in cancer cells, such as receptor tyrosine kinases (RTKs) which are involved in promoting growth and proliferation, Therefore inhibiting these proteins could impede cancer progression. An understanding of RTKs and the relevant signaling cascades, has enabled the development of many targeted drug therapies employing RTK inhibitors (RTKIs) some of which have entered clinical application. Here we discuss RTK structures, activation mechanisms and functions. Moreover, we cover the potential effects of combination drug therapy (including chemotherapy or immunotherapy agents with one RTKI or multiple RTKIs) especially for drug resistant cancers.

Genomic instability as a major mechanism for acquired resistance to EGFR tyrosine kinase inhibitors in cancer

Genomic instability as a major mechanism for acquired resistance to EGFR tyrosine kinase inhibitors in cancer

Predicting cardiotoxicity of cancer tyrosine kinase inhibitors with adult human primary cardiomyocytes

Predicting cardiotoxicity of cancer tyrosine kinase inhibitors with adult human primary cardiomyocytes

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy.

Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs. Finally, we discuss the interest of therapeutic combination of different RTKIs or with other molecules for personalized treatments, and the challenge for effective combination with less toxic and off-target effects.

Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics.

Tyrosine kinase inhibitors (TKIs) are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation–contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP) models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs.

How 'Optimal' are Optimal Sampling Times for Tyrosine Kinase Inhibitors in Cancer? Practical Considerations.

Tyrosine kinase inhibitors have been marketed as a fixed dose, 'one size fits all' treatment strategy. Physicians have also been interested in this method of dosing, knowing the complex planning of other current cancer therapies administered on a mg/m(2) or mg/kg basis and subsequent occurrence of dosing error or concern for underdosing. The 'simple and safe' strategy of a single dose of tyrosine kinase inhibitor for cancer has thus been widely adopted. However, the benefits purported to exist in the clinical trials do not appear to be borne out in clinical practice, particularly in solid tumours. In order to investigate whether pharmacokinetic variability is a contributor to the variable outcomes, pharmacokinetic targets to enable individualisation of tyrosine kinase inhibitor administration are now emerging. Evidence suggests there is not a clear relationship of a single dose to maximum plasma concentration (C max), steady-state trough concentration (C trough) or area under the curve (AUC). Furthermore, a significant number of questions remain related to the specific timing and frequency of sample collection required to achieve optimal outcomes. This article reviews the wide variability in the literature on this topic, specifically the different pharmacokinetic targets of the same drug for different cancers, for different states of cancer, and changing pharmacokinetic parameters over a treatment interval in cancer. It appears the optimal sampling times to enable appropriate dose recommendations across patients and diseases may vary, and are not always trough concentrations at steady state. Importantly, the need to be pragmatic in a clinical setting is paramount. Lastly, international collaborations to increase sample size are highly recommended to ensure enough patients are sampled to be sure of a clinical benefit from this concentration-directed methodology.

Therapeutic Innovations: Tyrosine Kinase Inhibitors in Cancer.

Conventional cytotoxic chemotherapy involving DNA-interacting agents and indiscriminate cell death is no longer the future of cancer management. While chemotherapy is not likely to completely disappear from the armamentarium; the use of targeted therapies in combination with conventional treatment is becoming the standard of care in human medicine. Tyrosine kinases are pivotal points of functional cellular pathways and have been implicated in malignancy, inflammatory, and immune-mediated diseases. Pharmaceutical interventions targeting aberrant tyrosine kinase signaling has exploded and is the second most important area of drug development. The “Valley of Death” between drug discovery and approval threatens to blunt the enormous strides in cancer management seen thus far. Kinase inhibitors, as targeted small molecules, hold promise in the treatment and diagnosis of cancer. However, there are still many unanswered questions regarding the use of kinase inhibitors in the interpretation and management of cancer. Comparative oncology has the potential to address restrictions and limitations in the advancement in kinase inhibitor therapy.

Clinical perspectives for irreversible tyrosine kinase inhibitors in cancer

Irreversible inhibitors provide potent and selective inhibition of tyrosine kinase enzymes. Use of such inhibitors has proved promising in overcoming the tumor resistance encountered with reversible tyrosine kinase inhibitors. Irreversible inhibitors inactivate their protein target through covalent interaction with a nucleophilic cysteine residue within the nucleotide binding pocket of the kinase domain.Different irreversible tyrosin kinase inhibitors directed against epidermal growth factor receptor (EGFR), Bruton's tyrosine kinase (BTK), vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor tyrosine kinase (FGFR) have been developed and some of them have been employed clinically as anticancer agents. This review focuses on recent preclinical and clinical progress with currently available irreversible tyrosine kinase inhibitors. The chemical structures of the candidates, structure-activity relationships, biological activities and results of current clinical investigations are described.

Abstract 1911: A common BIM polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

Abstract The use of tyrosine kinase inhibitors (TKI) to target oncogenic kinases has led to remarkable responses in patients with chronic myeloid leukemia (CML) and EGFR-mutated non-small cell lung cancer (EGFR NSCLC). However, a significant subset of patients have a minimal or very brief response. It has been suggested that germline polymorphisms may account for this upfront TKI resistance, and that identifying such polymorphisms will allow personalization of targeted therapy to achieve optimal responses in patients. Using paired-end DNA sequencing, we discovered a common (12.3% carrier rate) deletion polymorphism in intron 2 of the BIM gene. BIM is a pro-apoptotic member of the BCL2 family of proteins, and is required for TKIs to induce apoptosis in many cancers. We investigated the effects of the polymorphism on BIM function and TKI resistance in CML and EGFR NSCLC. Inspection of BIM gene structure suggested the polymorphism would result in mutually exclusive splicing of exon 3 (E3) and 4 (E4). Importantly, such an event is predicted to affect TKI sensitivity, since the pro-apoptotic BH3 domain is found only in E4. Using minigenes, we confirmed the deletion favored splicing of E3 over E4 by 5-fold (p=0.008), and that the deletion contained a cis-acting splicing suppressor. Next, using Zn finger nuclease-editing, we recreated the polymorphism in TKI sensitive CML (K562) and EGFR NSCLC (PC9) cell lines. Polymorphism-containing subclones had increased E3/E4 transcript ratios, decreased expression of BH3-containing BIM protein and defective apoptotic signaling, and were intrinsically TKI resistant. Importantly, while manipulation of E3-containing transcript levels did not alter the resistance phenotype, pharmacologic restoration of BH3 function (using a BH3 mimetic ABT-737) restored apoptotic signaling as well as TKI-sensitivity. Finally, we determined if the polymorphism predicted for inferior clinical responses in TKI-treated CML and EGFR NSCLC patients. In 203 CML patients, the polymorphism predicted inferior imatinib responses (defined by EuropeanLeukemiaNet criteria) among those with the polymorphism vs those without (odds ratio=2.94, p=0.02, 95% CI 1.17-7.43). In 141 EGFR NSCLC patients, the polymorphism predicted a shorter PFS of 6.6 vs 11.9 months (p=0.0027), and was independently prognostic for poorer PFS (hazard ratio=2.14, p=0.0026, 95% CI 1.30-3.50). In summary, by altering BIM splicing, the BIM polymorphism is sufficient to cause intrinsic TKI resistance in vitro, and predicts inferior TKI responses in patients. Upfront testing of CML and EGFR NSCLC patients for the BIM polymorphism may identify individuals at risk for developing clinical TKI resistance. Our results also offer an explanation for the heterogeneity of TKI responses among CML and EGFR NSCLC patients, and suggest the possibility of personalizing therapy with BH3 mimetics to improve TKI responses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1911. doi:1538-7445.AM2012-1911

A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.

Lapatinib: A novel EGFR/HER2 tyrosine kinase inhibitor for cancer

Lapatinib is an oral dual tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), both frequently overexpressed in human cancer. Preclinical data have shown that lapatinib is a potent and selective inhibitor of the tyrosine kinase domain of EGFR and HER2, and tumor cells that overexpress these receptors are growth inhibited by lapatinib both in vitro and in vivo. Phase I clinical trials have shown that lapatinib is well tolerated, with mild diarrhea and rash the most frequent toxicities, and early evidence of clinical efficacy has been reported especially in HER2-positive breast cancer. Phase II studies have shown activity for lapatinib in trastuzumab-refractory breast cancer either alone or in combination with trastuzumab. When used as first-line monotherapy for advanced breast cancer, objective tumor responses have been seen in 28% of patients with untreated HER2-positive advanced breast cancer. An extensive phase III program in advanced breast cancer is now in progress both for refractory disease and as first-line therapy in combination with chemotherapy with and without trastuzumab, and with endocrine therapy. Phase II studies have also been conducted in a variety of other tumors, including renal cell cancer. Parallel biomarker studies are starting to elucidate predictive molecular phenotypes that may indicate likelihood of response to lapatinib, and these may direct future trials with this oral tyrosine kinase inhibitor.

Epidermal growth factor receptor tyrosine kinase inhibitors in cancer therapy

Receptor tyrosine kinases are transmembrane proteins involved in signal transduction. They propagate growth factor signals from the cell surface to intracellular processes that control critical functions such as growth, differentiation, angiogenesis and inhibition of apoptosis. In malignancies, these signaling pathways are often exploited to optimize tumor growth and metastasis. One such family of receptor tyrosine kinases is the epidermal growth factor receptor (EGFR) tyrosine kinase. These receptors are overexpressed in a wide variety of epithelial cancers and have been implicated in tumor aggressiveness. Thus, targeting the EGFR tyrosine kinase has attracted considerable attention. This review will summarize current preclinical and clinical knowledge of the small-molecule oral inhibitors of the EGFR tyrosine kinase, which include ZD-1839, OSI-774, CI-1033, EKB-569, PKI-166, GW-2016 and BIBX-1382.