Mutational activation of the RAS/RAF/MEK/ERK and PI3K/AKT pathways is associated with colorectal cancer (CRC) progression and metastasis. Several small molecularly-targeted PI3K, AKT, RAF and MEK inhibitors have been tested in the clinic for the treatment of CRC but have shown only limited activity as a single agent. We have recently discovered that inhibition of both the ERK and AKT pathways exhibits potent, synergistic anti-CRC effects, both in vitro and in vivo, by effectively inhibiting eIF4E-initiated cap-dependent translation. Our overarching hypothesis is that the activation of cap-dependent translation by cooperative ERK and AKT signaling can selectively upregulate key oncoproteins that confer CRC progression and metastasis. By characterizing the molecular details of the activation of cap-dependent translation by cooperative ERK and AKT signaling, we aim to understand the molecular mechanisms underlying translational activation for CRC metastatic progression, and to explore the therapeutic applications of targeting translational regulation for CRC treatment.
Our Specific Aims are:
Aim 1. Determine the biologic and therapeutic consequences of translational activation by cooperative ERK and AKT signaling in CRC. We will determine 1) the extent to which the mTOR kinase integrates the function of ERK and AKT signaling in translational regulation of CRC cell growth and motility;2) how mTOR inhibition-induced feedback activation of ERK and AKT deregulates cap-dependent translation and causes mTOR-independence;and 3) the molecular basis of metastatic progression-modulated translational activity using our well-established orthotopic metastastic model of CRC.
Aim 2. Characterize the molecular mechanism of translational activation by cooperative ERK and AKT signaling for CRC progression and metastasis. We demonstrate that survivin is a key translational target of the ERK and AKT pathways. We will explore the possible mechanism by which the translationally-regulated survivin acts as an important growth/metastasis-promoting effector of these pathways. We will use combined polysome profiling and proteomic approaches to systematically identify other mRNAs that are selectively recruited to polysomes and translated by cooperative ERK and AKT signaling, and characterize in detail the functional importance of these genes in CRC progression and metastasis.
Aim 3. Evaluate the in vivo utility of combined inhibition of the MEK/ERK and AKT/mTOR pathways and targeting the convergence of their signals on translation initiation for enhancing CRC therapy. We will use both the mouse orthotopic model of CRC and the patient tumor-derived xenograft model to determine the effectiveness of MEK, AKT and mTOR inhibitors alone and in combination, and to characterize the ability of the translation initiation inhibitor 4EGI-1 to prevent tumor progressio and metastasis. The expression and modulation of eIF4E, 4E-BP1 and survivin, and their correlation with the mutational activation status of ERK and AKT pathways will also be characterized in response to the targeted therapies and in clinical specimens.

Public Health Relevance

The great majority of patients with metastatic colorectal cancer (CRC) is unresponsive to currently known therapy. This proposal aims to lay the groundwork for understanding the molecular mechanisms involved in the translational control of metastatic progression and treatment of CRC and is therefore of clinical relevance in itself, since new therapy for metastatic CRC is urgently needed. The overarching high impact of this proposal lies in the proof-of-concept that will be established for discovery of novel biomarkers and therapeutic targets for CRC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Snyderwine, Elizabeth G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
Goretsky, Tatiana; Bradford, Emily M; Ye, Qing et al. (2018) Beta-catenin cleavage enhances transcriptional activation. Sci Rep 8:671
Wang, Jun; Ye, Qing; Cao, Yanan et al. (2017) Snail determines the therapeutic response to mTOR kinase inhibitors by transcriptional repression of 4E-BP1. Nat Commun 8:2207
She, Qing-Bai; Gruvberger-Saal, Sofia K; Maurer, Matthew et al. (2016) Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer. BMC Cancer 16:587
She, Qing-Bai (2015) 4E-BP1 as an oncotarget. Aging (Albany NY) 7:517-8
Mi, Wenting; Ye, Qing; Liu, Side et al. (2015) AKT inhibition overcomes rapamycin resistance by enhancing the repressive function of PRAS40 on mTORC1/4E-BP1 axis. Oncotarget 6:13962-77
Zhang, Yinan; Ye, Qing; Wang, Xiachang et al. (2015) A divergent enantioselective strategy for the synthesis of griseusins. Angew Chem Int Ed Engl 54:11219-22
Wang, Jun; Ye, Qing; She, Qing-Bai (2014) New insights into 4E-BP1-regulated translation in cancer progression and metastasis. Cancer Cell Microenviron 1:
Ye, Q; Cai, W; Zheng, Y et al. (2014) ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. Oncogene 33:1828-39
Cai, Weijia; Ye, Qing; She, Qing-Bai (2014) Loss of 4E-BP1 function induces EMT and promotes cancer cell migration and invasion via cap-dependent translational activation of snail. Oncotarget 5:6015-27
Zhang, Yinan; Wang, Xiachang; Sunkara, Manjula et al. (2013) A diastereoselective oxa-Pictet-Spengler-based strategy for (+)-frenolicin B and epi-(+)-frenolicin B synthesis. Org Lett 15:5566-9