SIGNALING AND DRUG-SENSITIVITY

Even though alterations in receptor and nonreceptor kinases are involv ed in the development of human cancer, many cancer cell lines still re tain their responsiveness to growth factors. We have investigated the hypothesis that cellular signaling events regulate the sensitivity of cancer cells to chemotherapeutic agents. In 2008 human ovarian carcino ma cells, activation of a number of different transduction pathways re sulted in a 2 to 4-fold increase in the sensitivity to cisplatin. Thes e signaling events include pathways activated by the epidermal growth factor (EGF) receptor, tumor necrosis factor alpha (TNF alpha) recepto r, bombesin receptor, protein kinase A (PKA), and protein kinase C (PK C). Enhanced sensitivity to chemotherapeutic agents is presumed to be mediated by phosphorylation of critical target protein(s). beta-tubuli n has been identified as one such target for the protein kinase A sign aling cascade. For other signal transduction pathways the key substrat es that regulate drug sensitivity have not yet been identified. Recent work has shown that DNA damaging agents activate signaling cascades o ne of which involves the Src, Ras, and Raf proteins as intermediates a nd results in induction of a number of genes, including c-fos, c-jun, and the growth arrest and DNA damage-inducible (gadd) genes. This sign aling cascade has been shown to involve activation of protein kinase C and to have a protective function. With the growing understanding of how signaling events relate to damage response and drug sensitivity, n ew and potentially useful strategies for modulating drug sensitivity a re evolving.