Non-small cell lung cancer is often resistant chemotherapy and irradiation, but the molecular mechanisms that underlie this resistance are not well understood. Because growth factors offer protection against programmed cell death (apoptosis) in many other systems, we tested whether growth factor stimulated pathways are activated in non-small cell lung cancer (NSCLC) cells. We found that multiple signalling pathways are constitutively active in NSCLC cells, including kinase cascades stimulated by Ras such as Akt, as well as novel pathways that involve protein kinase C. Using inhibitors of these signalling pathways, we have shown that kinase inhibition causes apoptosis, and the combination of chemotherapy or irradiation with kinase inhibitors is additive. We are currently using genetic approaches to abrogate specific kinase activity to determine the role of individual kinases in Ras stimulated and PKC stimulated pathways in NSCLC cell survival. We are also testing whether phosphatase dysregulation (which results in constitutive kinase activity) plays a role in NSCLC survival. We will extend these studies to xenograft models in mice, and hope to identify novel targets that could be exploited in increase the effectiveness of chemotherapy or irradiation in patients with non-small cell lung cancer.
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