Oncotarget

Research Papers:

Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells

Qiaoling Song, Xiaoxiao Sun, Hui Guo and Qiang Yu _

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Oncotarget. 2017; 8:5003-5015. https://doi.org/10.18632/oncotarget.14009

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Abstract

Qiaoling Song1,2, Xiaoxiao Sun1,2, Hui Guo1,2, Qiang Yu1,2

1Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China

2University of Chinese Academy of Sciences, 100049 Beijing, China

Correspondence to:

Qiang Yu, email: qyu@sibs.ac.cn

Keywords: receptor tyrosine kinases, AKT, colorectal cancer, drug combination, RAS/RAF

Received: August 29, 2016     Accepted: December 07, 2016     Published: December 17, 2016

ABSTRACT

Receptor tyrosine kinase (RTK) signaling pathways are frequently activated in cancer cells due to mutations of RTKs and/or their downstream signaling proteins such as KRAS and BRAF. About 40% colorectal cancers (CRCs) contain KRAS or BRAF mutant genes and are resistant to treatments with individual inhibitors of RTKs, AKT, MEK, or BRAF. Therefore, an understanding of the molecular mechanisms of the drug resistance is necessary for developing effective strategies to treat the diseases. Here we report the discovery of an AKT/ERK reactivation mechanism that account for the cancer cell resistance to the AKT and MEK inhibitors treatments. The reactivations of AKT and ERK after the AKT or MEK inhibitor treatment were caused by a relief of an AKT or ERK-mediated feedback inhibition of the RTKs and/or their downstream pathways. A combination of RTK inhibitors, based on the RTK activation/phosphorylation profile, synergized with the AKT inhibitor, but not the MEK inhibitor, to completely inhibit the AKT phosphorylation and to block the growth of KRAS/BRAF mutant CRC cells. These results underscored the importance of AKT and the AKT feedback signaling to cancer cell growth and offered a novel therapeutic approach for the treatment of KRAS/BRAF mutant CRC cells.


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