Differential effects of kinase cascade inhibitors on neoplastic and cytokine-mediated cell proliferation

Raf promotes human herpesvirus-8 (HHV-8/KSHV) infection

“…UO126 inhibited MEK1/2 and ERK1/2 activity to a significant extent in cells, but this was not enough to lower infection to zero suggesting a possible role for signaling emanating from Raf kinase, other than the traditional MEK1/24ERK1/2 pathway. Such situations have been documented where Raf signaling may transmit its signaling through more than one intermediate (Janssen et al, 1998;Baumann et al, 2000;Shelton et al, 2003). Further, MEK inhibitors cannot suppress all the effects of Raf signaling.…”

Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy

“…It has been known for quite some time now, that treatment with certain inhibitors (for example, Raf inhibitors), can result in hyper-activation of wildtype (WT) Raf. 8,[146][147][148] It has recently become clear that it will be essential to determine the genetic status at both BRAF and RAS before treatment with B-Raf selective inhibitors proceeds. 149 Class I B-Raf inhibitors (active conformation inhibitors) such as PLX4720 and 885-A (a close analog of SB590885) will inhibit BRAF mutants, however, these ATP-competitive B-Raf inhibitors will not inhibit WT BRAF or mutant RAS.…”

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…Raf inhibitors have been developed [47][48][49][50][51] Figure 2 Genes mutated in hematopoietic cells, which result in sensitivity to targeted therapy. Activation of these molecules often results in dependence ('oncogene addiction') of the cells on the mutated gene for proliferation.…”