ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine.

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance.

LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer.

Activating mutations in the KRAS and BRAF genes, leading to hyperactivation of the RAS/RAF/MAPK oncogenic signaling cascade, are common in patients with colorectal cancer (CRC). While selective BRAF inhibitors are efficacious in BRAFmut melanoma, they have limited efficacy in BRAFmut CRC patients. In a RASmut background, selective BRAF inhibitors are contraindicated due to paradoxical activation of the MAPK pathway through potentiation of CRAF kinase activity.

Cloning and functional characterization of the rabbit C-C chemokine receptor 2.

Background: CC-family chemokine receptor 2 (CCR2) is implicated in the trafficking of blood-borne monocytes to sites of inflammation and is implicated in the pathogenesis of several inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. The major challenge in the development of small molecule chemokine receptor antagonists is the lack of cross-species activity to the receptor in the preclinical species. Rabbit models have been widely used to study the role of various inflammatory molecules in the development of inflammatory processes.

Regulation of sensitivity to TRAIL by the PTEN tumor suppressor.

The ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis preferentially in cancer cells is attractive for its development as a novel cancer therapeutic agent, but many cancer cell lines are resistant to TRAIL. While the molecular basis for TRAIL resistance is not always clear, a number of factors have been proposed to mediate TRAIL resistance, including decoy receptor, c-FLIP, nuclear factor (NF)-kappaB, and activation of antiapoptotic kinase signaling. Many growth factor receptors mediate their survival signals through the pathway involving recruitment and activation of phosphatidylinositol (PI) 3-kinase and the serine?threonine kinase Akt.

PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway.

The PTEN tumor suppressor is frequently mutated in human tumors. Loss of PTEN function is associated with constitutive survival signaling through the phosphatidylinositol-3 kinase/Akt pathway. Therefore, we asked if reconstitution of PTEN function would lead to the reversal of resistance to apoptosis in prostate cancer cells.

PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit.

PTEN is a lipid phosphatase responsible for down-regulating the phosphoinositide 3-kinase product phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate is involved in the activation of the anti-apoptotic effector target, Akt. Although the Akt pathway has been implicated in regulating NF-kappaB activity, it is controversial as to whether Akt activates NF-kappaB predominantly through mechanisms that regulate nuclear translocation or transactivation potential.