Evaluation of a tyrosine kinase peptide microarray for tyrosine kinase inhibitor therapy selection in cancer.

Personalized cancer medicine aims to accurately predict the response of individual patients to targeted therapies, including tyrosine kinase inhibitors (TKIs). Clinical implementation of this concept requires a robust selection tool. Here, using both cancer cell lines and tumor tissue from patients, we evaluated a high-throughput tyrosine kinase peptide substrate array to determine its readiness as a selection tool for TKI therapy.

Cross-resistance to clinically used tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib.

Purpose: When during cancer treatment resistance to a tyrosine kinase inhibitor (TKI) occurs, switching to another TKI is often considered as a reasonable option. Previously, we reported that resistance to sunitinib may be caused by increased lysosomal sequestration, leading to increased intracellular lysosomal storage and, thereby, inactivity. Here, we studied the effect of several other TKIs on the development of (cross-) resistance.

Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature.

Acquired resistance to anti-angiogenic tyrosine kinase inhibitors is an important clinical problem in treating various cancers. To what extent acquired resistance is determined by microenvironmental host-factors or by tumor cells directly is unknown. We previously found that tumor cells can become resistant to sunitinib in vitro.

The Potential Role of Lysosomal Sequestration in Sunitinib Resistance of Renal Cell Cancer.

Renal cell carcinoma (RCC) is a highly vascularized tumor type, which is often associated with inactivated mutations in the von Hippel-Lindau gene that drives proangiogenic signaling pathways. As such, new therapies for the treatment of RCC have largely been focused on blocking angiogenesis. Sunitinib, an antiangiogenic tyrosine kinase inhibitor, is the most frequently used first-line drug for the treatment of RCC.

Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance.

Purpose: Resistance to antiangiogenic tyrosine kinase inhibitors such as sunitinib is an important clinical problem, but its underlying mechanisms are largely unknown. We analyzed tumor sunitinib levels in mice and patients and studied sensitivity and resistance mechanisms to sunitinib.

Experimental Design: Intratumoral and plasma sunitinib concentrations in mice and patients were determined.

Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action?

Tyrosine kinases are important cellular signaling proteins that have a variety of biological activities including cell proliferation and migration. Multiple kinases are involved in angiogenesis, including receptor tyrosine kinases such as the vascular endothelial growth factor receptor. Inhibition of angiogenic tyrosine kinases has been developed as a systemic treatment strategy for cancer.

Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib.

Multiple molecular, cellular, micro-environmental and systemic causes of anticancer drug resistance have been identified during the last 25 years. At the same time, genome-wide analysis of human tumor tissues has made it possible in principle to assess the expression of critical genes or mutations that determine the response of an individual patient's tumor to drug treatment. Why then do we, with a few exceptions, such as mutation analysis of the EGFR to guide the use of EGFR inhibitors, have no predictive tests to assess a patient's drug sensitivity profile.