Tyrosine kinase inhibitors (TKIs)

A drug that inhibits tyrosine kinases, enzymes responsible for the activation of signal transduction cascades by phosphorylation of various proteins.

Used primarily as anti-cancer drugs.

Effective anti-tumor agents and anti-leukemic agents.

Include imatinib, erlotinib, gefitinib,lapatinib and sunitinib sorafenib,axitinib, and pazopanib.

The EGFR tyrosine kinase inhibitors are now standard first line treatments for EGFR mutation positive NSCLC, based on superior efficacy versus traditional chemotherapy.

Bind to receptors on epithelial or endothelial cells to block VEGF activity

Usually given as a front-line therapy for metastatic lung cancer with EGFR mutations, but resistance emerges after a median of 1 year.

Tyrosine kinase inhibitor resistance related to gate-keeper mutation of the EGFR gene (T790M mutation), MET gene amplification, MAPK gene amplification, P1KK3CA mutations, BRAF mutations, and AXL activation.

Acquired T790 M mutation in exon 20 is the most common cause of resistance to the EGFR-TKI therapy.

Premature stoppage of EGFR TKI therapy may be associated with rapid progression of symptoms and tumor regrowth, and its reintroduction of TKI therapy may lead to decreased tumor growth.

EGFR TKIs toxicities include: rash, fatigue, headaches, fluid retention, gastrointestinal toxicity, hepatic and pulmonary toxicity.

Rash is an adverse effect specific to all agents that block the EGFR pathway, including small molecules and monoclonal antibodies.

The epidermis has a high level of EGFR expression.

Use of TKIs associated with higher risk of vascular events.

Long term side effects include cardiovascular events and pulmonary hypertension.

ALK positive TKIs for NSCLC-crizotinib, ceritinib, alectinib, brigatinib, and loratinib with first, second and third line inhibitors.



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