EXPLORING IKKbeta KINASE AS AN ANTI-METASTATIC THERAPEUTIC TARGET IN KRAS-INDUCED LUNG CANCER

Abstract

The most common genetic abnormalities found in lung cancer are activating mutations in the KRAS oncogene. Even though these mutations have been causally linked to the oncogenic process, therapies targeted to oncogenic RAS have sofar failed. Therefore, in order to select better targets for lung cancer therapy, one will need to identify key cancer-relevant KRAS downstream pathways involved in promoting malignant behaviour. One of the critical characteristics of malignant behaviour is the acquisition of metastatic capability. Based on recent work showing that oncogenic KRAS promotes, not only tumor initiation, but also the acquisition of a metastatic phenotype, our objective is to identify therapeutic targets in lung cancer that can be explored to inhibit KRAS-induced metastasis. The first hypothesis of this project is that KRAS-induced lung cancer metastatic behaviour is promoted by IKK² kinase, and, therefore, that IKK² inhibition will reduce lung cancer cell invasiveness in vitro and lung tumor metastatic growth in vivo. The second hypothesis of this project is that IKK² promotes metastatic behaviour by promoting a cancer stem cell phenotype. These hypotheses were formulated on the basis of previous studies showing that, not only IKK² pharmacological inhibition blocks breast and prostate cancer stem cell self-renewal, but also that the main IKK² substrate, the transcription factor NF-ºB, promotes metastasis in different tumor models, that NF-ºB is activated by KRAS in lung tumors in situ in an IKK²-dependent manner, and that pharmacological IKK² inhibition in a KRAS-induced lung cancer mouse model reduces lung tumor growth and progression to higher histological grades. The rationale that drives this research project is that it is expected to shed light on the molecular mechanism involved in the acquisition of metastatic behaviour induced by KRAS. In addition, we expect to validate new strategies for KRAS-induced lung cancer therapy. (AU)