Targeting Translation Dependence in Colorectal Cancer Progression

Mutational activation of both RAS/RAF/MEK/ERK and PI3K/AKT pathways is a common feature of colorectal cancer (CRC) associated with poor prognosis, and is required for tumor progression and metastasis. Selective inhibitors of RAF/MEK/ERK and PI3K/AKT signaling are already being tested in the clinic. However, the activities of these inhibitors as single agent are still limited in CRC. Recently, we have reported the novel finding that the resistance to inhibition of either RAS/ERK or PI3K/AKT pathway in CRC is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by both pathways (She et al., Cancer Cell, 2010). Combined inhibition of both pathways is required to effectively inhibit cap-dependent translation associated with the synergistic antitumor activity in CRC. Thus, the cap-dependent translation apparatus functions as a key molecular switch that integrates function of both pathways in CRC progression. Additionally, our preliminary data further provide evidence that the activation of cap-dependent translation is also essential for enhancing cell migration, invasion and metastatic potential of CRC. The mTOR kinase is a downstream target of both ERK and AKT signaling, and plays an important role in regulation of cap-dependent translation. However, we and other have shown that inhibition of mTOR induces feedback activation of AKT and ERK. Notably, we have identified that survivin is a preferentially-translated protein by cooperative MEK/ERK and AKT/mTOR signaling, and involves in CRC cell growth and motility. Collectively, these findings led us to the central hypothesis that the activation of capdependent translation by cooperative ERK and AKT signaling is required to selectively upregulate key oncoproteins that mediate CRC progression and metastasis. The goals of this project are to elucidate the molecular mechanisms underlying the translational activation for metastatic progression of CRC and to explore the therapeutic applications of targeting translational regulation as a novel therapy for CRC. Specifically, in Aim 1, we will determine whether mTOR integrates the function of ERK and AKT signaling in translational regulation of cell survival and motility of CRC, whether the feedback activation of ERK and AKT by mTOR inhibition affects cap-dependent translation and causes mTOR-independence. The contributions of translational activation to metastatic progression will be further defined in the mouse orthotopic model of CRC. In Aim 2, we will determine whether the translationally regulated survivin is a dominant growth/metastasispromoting effector of ERK and AKT pathways. We will then use polysome profiling and proteomic approaches to systematically identify which mRNAs are selectively recruited to polysomes and translated by cooperative ERK and AKT signaling. The prioritized candidate genes will be characterized for their functional relevance and mechanism involved in CRC progression and metastasis. In Aim 3, we will define whether combined inhibition of MEK/ERK and AKT/mTOR pathways or targeting the convergence of their signals on translation initiation will constitute an effective treatment for blocking progression and metastasis of CRC in mouse orthotopic and patient tumor-derived xenograft models. These proposed studies will provide novel insights into the biology and clinical relevance of translational regulation in CRC metastatic progression and therapy. These insights will lead to the discovery of new targets beyond a narrow focus on the transcriptional regulation, and facilitate the development of new strategies to prevent and suppress metastatic progression of CRC.