T790M , also known as Thr790Met , is a gatekeeper mutation of the epidermal growth factor receptor (EGFR). The mutation substitutes a threonine (T) with a methionine (M) at position 790 of exon 20, affecting the ATP binding pocket of the EGFR kinase domain. Threonine is a small polar amino acid ; methionine is a larger nonpolar amino acid. Rather than directly blocking inhibitor binding to the active site, T790M increases the affinity for ATP so that the inhibitors are outcompeted; irreversible covalent inhibitors such as osimertinib can overcome this resistance.
21-764: Over 50% of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) is caused by a mutation in the ATP binding pocket of the EGFR kinase domain involving substitution of a small polar threonine residue with a large nonpolar methionine residue, T790M. In November 2015, the US FDA granted accelerated approval to osimertinib (Tagrisso) for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation -positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, which progressed on or after EGFR TKI therapy. This biochemistry article
42-442: A Wee1 kinase inhibitor that is undergoing numerous clinical trials in the treatment of refractory solid tumors. However, toxicities such as myelosuppression , diarrhea , and supraventricular tachyarrhythmia have arisen while attempting to determine the toxicity and effectiveness of the drug. Lapatinib , FDA-approved for treatment in conjunction with chemotherapy or hormone therapy, is also currently undergoing clinical trials in
63-429: A phosphate group to the protein ( phosphorylation ), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia . They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis . They are also called tyrphostins , the short name for " tyrosine phosphorylation inhibitor ", originally coined in
84-419: A 1988 publication, which was the first description of compounds inhibiting the catalytic activity of the epidermal growth factor receptor (EGFR). The 1988 study was the first demonstration of a systematic search and discovery of small-molecular-weight inhibitors of tyrosine phosphorylation, which do not inhibit protein kinases that phosphorylate serine or threonine residues and can discriminate between
105-414: A somewhat complex and rather specific initial indication for lapatinib—use only in combination with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab. Early clinical trials have been performed suggesting that high dose intermittent lapatinib might have better efficacy with manageable toxicities in
126-401: A taxane and trastuzumab) demonstrated that administrating lapatinib in combination with capecitabine delayed the time of further cancer growth compared to regimens that use capecitabine alone. The study also reported that risk of disease progression was reduced by 51%, and that the combination therapy was not associated with increases in toxic side effects. The outcome of this study resulted in
147-939: Is a protein kinase inhibitor shown to decrease tumor-causing breast cancer stem cells . Lapatinib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFR/HER2 protein kinase domain , preventing self- phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinase#Signal transduction ). Lapatinib is used as a treatment for women's breast cancer in treatment-naïve, ER+/EGFR+/HER2+ breast cancer patients and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as anthracycline , taxane -derived drugs, or trastuzumab (Herceptin). A 2006 GSK-supported randomized clinical trial on female breast cancer previously being treated with those agents (anthracycline,
168-425: Is a stub . You can help Misplaced Pages by expanding it . This genetics article is a stub . You can help Misplaced Pages by expanding it . Tyrosine kinase inhibitor A tyrosine kinase inhibitor ( TKI ) is a pharmaceutical drug that inhibits tyrosine kinases . Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding
189-449: The Cdc37 - Hsp90 molecular chaperone system on which they depend for their cellular stability, leading to their ubiquitylation and degradation. Signal transduction therapy can also be used for non-cancer proliferative diseases and for inflammatory conditions. An example is nintedanib for the treatment of idiopathic pulmonary fibrosis . Lapatinib Lapatinib ( INN ), used in
210-531: The U.S. Food and Drug Administration (FDA) approved lapatinib in combination therapy for breast cancer patients already using capecitabine (Xeloda). In January 2010, Tykerb received accelerated approval for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated (in combination with letrozole ). Pharmaceutical company GlaxoSmithKline (GSK) markets
231-501: The drug under the proprietary names Tykerb (mostly U.S.) and Tyverb (mostly Europe and Russia). The drug currently has approval for sale and clinical use in the US, Australia, Bahrain, Kuwait, Venezuela, Brazil, New Zealand, South Korea, Switzerland, Japan, Jordan, the European Union, Lebanon, India and Pakistan. In August 2013, India's Intellectual Property Appellate Board revoked
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#1733085340664252-570: The form of lapatinib ditosylate ( USAN ) (trade names Tykerb and Tyverb marketed by Novartis ) is an orally active drug for breast cancer and other solid tumours . It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2). In March 2007,
273-527: The kinase domains of the EGFR and that of the insulin receptor . It was further shown that in spite of the conservation of the tyrosine-kinase domains one can design and synthesize tyrphostins that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative HER2 . Numerous TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti- tumor agents and anti- leukemic agents. Based on this work imatinib
294-617: The patent for Glaxo's Tykerb citing its derivative status, while upholding at the same time the original patent granted for lapatinib. The drug lapatinib ditosylate is classified as S/NM (a synthetic compound showing competitive inhibition of the natural product) that is naturally derived or inspired substrate. Lapatinib inhibits the tyrosine kinase activity associated with two oncogenes , EGFR (epidermal growth factor receptor) and HER2/neu (human EGFR type 2). Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women. Like sorafenib , lapatinib
315-435: The primary endpoint of improved overall survival (OS) against chemotherapy alone. The trial did not discover new safety signals, while the median OS for patients in the lapatinib and chemotherapy group was 12.2 months against 10.5 months for patients in the placebo plus chemotherapy. Secondary endpoints of the randomized, double-blinded study, were progression-free survival (PFS), response rate and duration of response. Median PFS
336-403: The treatment of HER2 -overexpressing breast cancers as it is suggested intermittent high-dose therapy might have better efficacy with manageable toxicity than the standard continuous dosing. A Phase I clinical trial found responses and dramatic responses to this line of treatment, with the most common toxicity being diarrhea. Imatinib, sunitinib, sorafenib , and pazopanib have been studied in
357-417: The treatment of HER2 -overexpressing breast cancers. Like many small molecule tyrosine kinase inhibitors, lapatinib is regarded as well tolerated. The most common side effects reported are diarrhea , fatigue , nausea and rashes . Of note, lapatinib related rash is associated with improved outcome. In clinical studies elevated liver enzymes have been reported. QT prolongation has been observed with
378-425: The treatment of aggressive fibromatosis (desmoid tumor). TKIs operate by four different mechanisms: they can compete with adenosine triphosphate (ATP), the phosphorylating entity, the substrate or both or can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change . Recently TKIs have been shown to deprive tyrosine kinases of access to
399-496: The use of lapatinib ditosylate but there are no reports of torsades de pointes . Caution is advised in patients with hypokalaemia, hypomagnesaemia, congenital long QT syndrome, or with coadministration of medicines known to cause QT prolongation. In combination with capecitabine , reversible decreased left ventricular function are common (2%). Phase III study designed to assess lapatinib in combination with chemotherapy for advanced HER2-positive gastric cancer in 2013 failed to meet
420-461: Was 6 months, response rate was 53% and the duration of response was 7.3 months in the investigational combination chemotherapy group compared to median PFS of 5.4 months, response rate of 39% and duration of response of 5.6 months for patients in chemotherapy alone group. Diarrhoea, vomiting, anemia, dehydration and nausea were serious adverse events (SAE) reported in over 2% of patients in the investigational combination chemotherapy group, while vomiting
441-446: Was developed against chronic myelogenous leukemia (CML) and later gefitinib and erlotinib aiming at the EGF receptor. Dasatinib is a Src tyrosine kinase inhibitor that is effective both as a senolytic and as therapy for CML. Sunitinib , an inhibitor of the receptors for FGF , PDGF and VEGF is also based on early studies on TKIs aiming at VEGF receptors . Adavosertib is
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