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Identification of a Small Molecule with Synthetic Lethality for K-Ras and Protein Kinase C Iota

Departments of ¹ Thoracic and Cardiovascular Surgery and ² Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Bingliang Fang, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 445, Houston TX 77030. Phone: 713-563-9147; Fax: 713-794-4901; E-mail: Bfang{at}mdanderson.org.

Key Words: synthetic lethality • cancer • K-ras • PKC

K-Ras mutations are frequently found in various cancers and are associated with resistance to treatment or poor prognosis. Similarly, poor outcomes have recently been observed in cancer patients with overexpression of protein kinase C iota (PKC), an atypical protein kinase C that is activated by oncogenic Ras protein and is required for K-Ras–induced transformation and colonic carcinogenesis in vivo. Thus far, there is no effective agent for treatment of cancers with K-Ras mutations or PKC overexpression. By synthetic lethality screening, we identified a small compound (designated oncrasin-1) that effectively kills various human lung cancer cells with K-Ras mutations at low or submicromolar concentrations. The cytotoxic effects correlated with apoptosis induction, as was evidenced by increase of apoptotic cells and activation of caspase-3 and caspase-8 upon the treatment of oncrasin-1 in sensitive cells. Treatment with oncrasin-1 also led to abnormal aggregation of PKC in the nucleus of sensitive cells but not in resistant cells. Furthermore, oncrasin-1–induced apoptosis was blocked by siRNA of K-Ras or PKC, suggesting that oncrasin-1 is targeted to a novel K-Ras/PKC pathway. The in vivo administration of oncrasin-1 suppressed the growth of K-ras mutant human lung tumor xenografts by >70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity. Our results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents, which effectively kill K-Ras mutant cancer cells. [Cancer Res 2008;68(18):7403–8]

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