Oncogenic K-ras “addiction” and synthetic lethality

Mutational activation of the K-ras gene is a frequent oncogenic event in human cancers, associated with poor clinical prognosis and resistance to treatment.Despite efforts to develop therapeutics that target K-ras or its downstream effector molecules, clinical benefit in this setting has not yet been achieved.An alternative approach to K-ras mutant cancers involves the identification of genes that selectively drive the maintenance of tumors that are "addicted" to or dependent on mutant K-ras.Disruption of these genes would result in "synthetic lethality" specifically in cancer cells driven by mutant K-ras, thereby potentially sparing non-tumor cells.Through this approach, three recent reports have identified PLK1, STK33, SYK, RON and integrin β6 as previously unappreciated pharmacologically tractable targets in the setting of K-ras activation, which drive growth and survival selectively in K-ras-dependent cancer cells.K-ras mutations are among the most frequent oncogenic events in human cancers, most often seen in adenocarcinomas of the lung, pancreas and colon, 1 and K-ras mutant cancers are notoriously refractory to available therapies.K-ras is a small GTPase with binary molecular switch functionality, which upon activation engages effectors such as the Raf and PI3 kinases, thereby stimulating signaling cascades 2 that can impact proliferation, apoptosis and differentiation. 3K-ras mutational activation in mouse models of tumorigenesis drives neoplastic and malignant progression. 4Thus, mutational activation of K-ras is a well established tumor-initiating event, underscored by the observation that K-ras mutations arise in early pre-neoplastic lesions. 5,6 However, it is unclear whether K-ras activity is required for tumor maintenance during later stages of malignant progression.Transgenic mouse models of Myc-or Ras-induced oncogenesis, in which these