(2010). PAK1 as a therapeutic target. Expert Opinion on Therapeutic Targets: Vol. 14, No. 7, pp. 703-725.

The activity of protein kinase B, also known as Akt, is commonly elevated in human malignancies and plays a crucial role in oncogenic transformation. The relationship between Akt and the mitogen-activated protein kinase cascade, which is also frequently associated with oncogenesis, remains controversial. We report here examples of cooperation between Akt and cRaf in oncogenic transformation, which was accompanied by elevated activity of extracellular signal-regulated mitogen-activated protein kinases. The effect of Akt on extracellular signal-regulated kinases depended on the status of p21-activated kinase (PAK). Importantly, disruption of the function of PAK not only uncoupled the activation of Akt from that of extracellular signal-regulated kinases, but also greatly reduced the capacity of Akt to act as a transforming oncogene. For the malignancies with hyperactive Akt, our observations support the role for PAK-1 as a potential target for therapeutic intervention.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Ruchi Singhal1 and Eugene S. Kandel1* 1 Roswell Park Cancer Institute, Department of Cell Stress Biology, Elm & Carlton St., Buffalo, NY, 142263, USA * Corresponding author Correspondence: Eugene S. Kandel, email: // <![CDATA[ mail("Eugene.Kandel","RoswellPark",1,""); // ]]> Keywords: IPA3, PAK1, BRAF, NRAS, KRAS, melanoma, colon cancer, GDC-0879, AZD6244 Received: July 15, 2012, Accepted: July 30, 2012, Published: July 31, 2012 Abstract While new drugs aimed at BRAF-mutated cancers are entering clinical practice, cells and tumors with activating Ras mutations are relatively resistant to those and quite a few other anti-cancer agents. This inspires the effort to reverse this resistance or to uncover new vulnerabilities in such resistant cancers. IPA3 has been originally identified as a small molecule inhibitor of p21-activated protein kinase 1 (PAK1), a candidate therapeutic target in human malignancies. We have tested a battery of melanoma and colon carcinoma cell lines that carry mutations in BRAF, NRAS and KRAS genes and have observed that those with NRAS and KRAS mutations are more sensitive to killing by IPA3. Genetic manipulations suggest that the differential response depends not just on these oncogenes, but also on additional events that were co-selected during tumor evolution. Furthermore, sublethal doses of IPA3 or ectopic expression of dominant-negative PAK1 sensitized Ras-mutated cells to GDC-0897 and AZD6244, which otherwise have reduced efficiency against cells with activated Ras. Dominant-negative PAK1 also reduced the growth of NRAS-mutated cells in confluent cultures, but, unlike IPA3, caused no significant toxicity. Although it remains to be proven that all the effects of IPA3 are exclusively due to inhibition of PAK1, our findings point to the existence of selective vulnerabilities, which are associated with Ras mutations and could be useful for better understanding and treatment of a large subset of tumors.

Malignant melanoma claims more lives than any other skin malignancy. While primary melanomas are usually cured via surgical excision, the metastatic form of the disease portents a poor prognosis. Decades of intense research has yielded an extensive armamentarium of anti-melanoma therapies, ranging from genotoxic chemo- and radiotherapies to targeted interventions in specific signaling pathways and immune functions. Unfortunately, even the most up-to-date embodiments of these therapies are not curative for the majority of metastatic melanoma patients, and the need to improve their efficacy is widely recognized. Here, we review the reports that implicate p21-regulated kinase 1 (PAK1) and PAK1-related pathways in the response of melanoma to various therapeutic modalities. Ample data suggest that PAK1 may decrease cell sensitivity to programmed cell death, provide additional stimulation to growth-promoting molecular pathways, and contribute to the creation of an immunosuppressive tumor microenvironment. Accordingly, there is mounting evidence that the concomitant inhibition of PAK1 enhances the potency of various anti-melanoma regimens. Overall, the available information suggests that a safe and effective inhibition of PAK1-dependent molecular processes would enhance the potency of the currently available anti-melanoma treatments, although considerable challenges in implementing such strategies still exist.

MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade