Abstract Mutational activation of the PI3K/AKT and RAS/RAF/MEK/ERK pathways is associated with colorectal cancer (CRC) progression and metastasis. Several small-molecule inhibitors of PI3K, AKT, RAF and MEK have been tested in the clinic for the treatment of CRC but have shown only limited activity as a single agent. We find that a potential mechanism of AKT or ERK-independence is associated with redundant activation of eIF4E-initiated cap-dependent translation mediated by convergent regulation of the translation repressor 4E-BP1 by the AKT and ERK pathways. Combined inhibition of both pathways exhibits synergistic anti-CRC effects, both in vitro and in vivo, by effectively inhibiting cap-dependent translation via maximal activation of 4E-BP1 function. Specifically, we identify that survivin is a key translationally-regulated target of both pathways through convergence on the mTORC1/4E-BP1/eIF4E axis, and continuous translation of survivin by AKT and ERK signaling is crucial for CRC progression to metastasis. These findings reveal that the cap-dependent translation functions as a critical regulatory node that integrates oncogenic AKT and ERK signals for metastatic progression of CRC. Thus, targeting cap-dependent translation that could simultaneously block upstream oncogenic signals and their downstream targets may provide a promising therapeutic strategy for advanced CRC. Citation Format: Qing Ye, Weijia Cai, B. Mark Evers, David Solit, Neal Rosen, Qing-Bai She. Role of cap-dependent translation in response to upstream kinase-targeted therapy in colorectal cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A22.