Investigating the role of IKKbeta kinase and ERBB in the maintenance of the cancer stem-like phenotype in KRAS-driven lung cancer

Abstract

Lung cancer induced by oncogenic mutations of the KRAS GTPase is a very frequent disease, for which there are currently no effective therapies. Although these mutations are closely linked to oncogenesis, small molecules to inhibit RAS proteins effectively in the clinic still do not exist. Therefore, for better therapeutic targets for lung cancer to become available, it is necessary to identify the molecular mechanisms by which oncogenic KRAS regulates the maintenance and progression of the malignant phenotype. One of the most significant characteristics of malignant behaviour is the acquisition of a cancer stem-like phenotype by tumour-initiating cells (TICs). TICs are defined as a subpopulation of self- renewing tumour cells able to initiate tumour formation and sustain tumour growth. They are also resistant to chemo- and radiotherapy and it is believed that they are responsible for tumour recurrence and metastatic dissemination. The development of new therapeutic approaches targeting these cells is essential for improving the efficacy of current anti-tumour therapies. We have previously shown that IKK² is activated downstream of KRAS in lung cells, and inhibition of IKK² activity in an animal model of KRAS-induced lung cancer decreases tumour growth, as well as prevents tumour progression to more advanced histological grades. Interestingly, recent data from the Oncogene-Induced Vulnerabilities Laboratory lead by Dr Daniel J Murphy (Institute of Cancer Sciences, University of Glasgow, UK) indicates a critical role for the ERBB RTK signal transduction pathway, which functions upstream of KRAS, in supporting KRAS-driven lung tumourigenesis/carcinogenesis. Since KRAS-mediated signalling has been implicated in the expansion and maintenance of CITs, the aim of this project is to explore whether inhibition of upstream and/or downstream pathways of oncogenic KRAS can reduce the stem- like phenotype of lung cancer cells, thereby providing a potential new approach for lung cancer therapy design. (AU)