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

Abstract

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 (PKCI), 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 PKCI 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 PKCI in the nucleus of sensitive cells but not in resistant cells. Furthermore, oncrasin-1-induced apoptosis was blocked by siRNA of K-Ras or PKCI, suggesting that oncrasin-1 is targeted to a novel K-Ras/PKCI 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]

Protein Kinase C (PKC) Isozymes and Cancer

“…In addition, aurothiomalate decreases the proliferation of lung cancers by inhibition of MEK/ERK signaling [311]. Interestingly, oncrasin-1, a small molecule RNA polymerase II inhibitor, requires K-Ras or PKC for its apoptosis induction in lung cancer cells [319].…”

Ethanolic extract of Condurango (Marsdenia condurango) used in traditional systems of medicine including homeopathy against cancer can induce DNA damage and apoptosis in non small lung cancer cells, A549 and H522, in vitro

“…NSCLC accounts for >80% of all lung cancers and is responsible for more deaths from cancer than any other tumor types (Jemal et al, 2005). This type of cancer hardly responds to chemotherapy, primarily because of its KRAS mutation that often makes it resistant to chemotherapy (Guo et al, 2008). Traditionally surgery, radiation therapy, and chemotherapy are the ultimates to treat patients with NSCLC.…”

Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress

“…In the case of oncogenic K-ras, several compounds have already been identified, including sulfinyl cytidine derivative (SC-D) (13), erastin (for eradicator of RAS and ST-expressing cells) (14), and oncrasin-1 (for oncogenic Ras tumor-inhibiting compound 1) (15). Though erastin has been shown to induce mitochondrial dysfunction (16), and oncrasin may require protein kinase C iota (PKCι) for activity (15), the precise mechanisms by which any of these compounds selectively kill K-ras mutant cells remain uncertain. Recently, synthetic lethal screens using shRNAs targeting the kinome have identified other potential target pathways in K-ras mutant cell lines, including the noncanonical IκB kinase TBK1 involved in NF-κB signaling (17), the mitotic kinase PLK1 (18), and the serine/threonine protein kinase STK33 of unknown biological function (19).…”