Rewiring Signaling Networks to Evade Chemotoxicity
21 November 2012
Leslie K. Ferrarelli, Nancy R. Gough
Michael Yaffe (Koch Institute at MIT), organizer of the symposium, highlighted the shortcomings of the traditional approach to translating signaling knowledge into clinical therapies. He likened cell signaling networks to electrical circuitry: The phospho group is the current, and the kinase-driven phosphorylation cascades are the voltage. Electricians would not measure the current and voltage and assume that they know how the circuitry works or how to manipulate it; however, many current cancer strategies are based on monitoring one or a few phosphorylation events and targeting a single kinase without having knowledge of the entire network. These highly specific, kinase-directed strategies often ultimately fail, resulting in the rapid emergence of a drug-resistant tumor. Yaffe described how using a sequential approach to combination therapies exploited the ability of cancer cells to rewire their signaling circuitry by first "herding" the cells down a selected pathway with kinase inhibitors and then "clobbering" them with a lethal secondary hit, for example with a DNA-damaging agent.
Joan Brugge (Harvard Medical School), highlighting her laboratory’s work with three-dimensional (3D) cultures of ovarian cancer, described the resistance mechanisms in cancer. Exposure of tumor cells, growing as 3D spheroids with an internal group of cells that do not contact the extracellular matrix and an external layer of cells that contact extracellular matrix, to a phosphoinositide 3-kinase (PI3K) inhibitor resulted in death of the internal cells, but survival of the cells contacting the extracellular matrix. Subsequently, the outer cells exhibited network rewiring that allowed them to invade the tumor cavity and re-establish cells inside the tumor cavity, which could possibly represent not only a resistance mechanism, but also a mechanism for metastasis. She further described how an overlooked consequence of kinase inhibition is the loss of inhibitory feedback loops, thus activating adaptive antiapoptotic signaling and growth factor pathways. Brugge suggested that phosphoproteomic analysis of cancer cells after drug treatment may reveal specific combination therapies that could prevent cancer cells from mounting the adaptive response to kinase inhibition. Her work highlights the importance of targeting both and the signaling kinase and the adaptive stress response.
Jeffrey Settleman (Genentech) emphasized the importance of nongenetic means of chemotherapy resistance, that is resistance that does not involve genetic mutation. Culturing cancer cells for long periods in the presence of specific kinase inhibitors can produce drug-resistant clones, which have altered epigenetic chromatin modifications. He speculated that there may be intermediate states of drug resistance that can be reversed and that these may represent therapeutic "windows of opportunity." Thus, drugs that reverse or prevent these epigenetic changes (such as deacetylation and methylation) may be effective complements to kinase inhibition in treating cancer and reducing resistance. He also showed that the presence of various growth factors can influence the efficacy of kinase inhibitors in producing cell death of cultured cancer cells. Because secreted growth factors can be measured in plasma and these may represent mechanisms for subverting the toxicity of the targeted therapy, analysis of growth factor concentrations in patient’s circulation may present an opportunity for personalized treatment strategies. By targeting not only the kinase to which the cancer cells are “addicted” but other growth factor pathways that may rescue the cells from kinase inhibition, more effective combinations tailored to the individual may be created.
Michael Comb (President and CEO of Cell Signaling Technology) discussed current efforts to characterize the human "kinome," the array of posttranslational modifications and understand how these changes affect signaling networks. The initial studies involved analysis of phosphorylation in signaling pathways using antibodies specific for particular phosphorylated motifs to screen for changes in protein phosphorylation in response to kinase inhibition. Recent work has focused on other posttranslational modifications and how these change in response to kinase inhibition. Current efforts use a bidirectional approach, combining both DNA sequencing and protein mass spectrometry to identify the mutational changes and posttranslational modifications that converge on signaling pathways in cancer and disease.
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