Taking out the JNK: A window of opportunity to improve cancer therapy.

c-JUN-N-terminal kinase (JNK) signaling is a stress-induced response that enables survival of normal cells and is also utilized by cancer cells to evade therapy. Combining JNK inhibitors with standard therapies provides a potential strategy for overcoming drug resistance. Use of the optimal combination dosing and scheduling may substantially improve outcomes for cancer patients.

The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma.

Most patients with BRAF-mutant metastatic melanoma display remarkable but incomplete and short-lived responses to inhibitors of the BRAF kinase or the mitogen-activated protein kinase kinase (MEK), collectively BRAF/MEK inhibitors. We found that inherent resistance to these agents in BRAF(V600)-mutant melanoma cell lines was associated with high abundance of c-JUN and characteristics of a mesenchymal-like phenotype. Early drug adaptation in drug-sensitive cell lines grown in culture or as xenografts, and in patient samples during therapy, was consistently characterized by down-regulation of SPROUTY4 (a negative feedback regulator of receptor tyrosine kinases and the BRAF-MEK signaling pathway), increased expression of JUN and reduced expression of LEF1.

Phenotype switching in melanoma: implications for progression and therapy.

Epithelial-mesenchymal transition (EMT) is a key process associated with the progression of epithelial cancers to metastatic disease. In melanoma, a similar process of phenotype switching has been reported and EMT-related genes have been implicated in promotion to a metastatic state. This review examines recent research on the role of signaling pathways and transcription factors regulating EMT-like processes in melanoma and their association with response to therapy in patients, especially response to BRAF inhibition, which is initially effective but limited by development of resistance and subsequent progression.

Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro.

Elevated expression of multidrug efflux pumps such as P-glycoprotein (Pgp) have been associated with resistance to cytotoxic drugs used in the treatment of leukemias and other cancers. Imatinib mesylate (STI-571 or Gleevec) is a potent inhibitor of the BCR/ABL and c-KIT tyrosine kinases. It has displayed considerable efficacy in treatment of patients with Philadelphia-positive acute lymphoblastic leukemia and chronic myelogenous leukemia and those with gastrointestinal stromal tumors (GISTs).

Constitutively active mutant D816VKit induces megakayocyte and mast cell differentiation of early haemopoietic cells from murine foetal liver.

Mutations of Kit at position D816 have been implicated in mastocytosis, acute myeloid leukaemia and germ cell tumours. Expression of this mutant Kit in cell lines results in factor-independent growth, differentiation and increased survival in vitro and tumourigenicity in vivo. Mutant D816VKit and wild-type Kit were expressed in murine primary haemopoietic cells and grown in stem cell factor (SCF) or the absence of factors.

Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant.

Imatinib (Glivec; STI571) is an ATP-competitive kinase inhibitor of c-Abl, BCR/ABL, c-Kit, and platelet-derived growth factor receptor. Overexpression or constitutive activation of Kit by mutations have been associated with various malignancies. Mutations in the intracellular juxtamembrane region of Kit (e.