title: Combination of cetuximab and PP242 synergistically suppress the progression of wild-type KRAS colorectal carcinoma.
abstract: Mammalian target of rapamycin (mTOR) has been shown to be overactive in human colorectal cancer, but the first-generation mTOR inhibitor, rapamycin, has failed to show clinical efficacy against colorectal cancer. On the other hand, although the second-generation mTOR inhibitor, PP242, has exerted substantial efficacy, it was revealed that independent inhibition by PP242 was transient, which could lead to positive-feedback loop to EGFR. Using wild-type KRAS colorectal cancer cells as models, we investigate the treatment efficacy of a widely used anti-EGFR monoclonal antibody, cetuximab, and PP242, alone or in combination in vitro and in vivo. Results of cell viability assays confirmed the synergistic inhibitory effect of PP242 and cetuximab on the survival of Caco-2 and HT-29 cells. Moreover, the ability of cancer-cell invasion and proliferation was also significantly inhibited by the combination therapy when compared with cetuximab or PP242 alone. Interestingly, the percentage of CD44-positive cancer cells was substantially decreased by the combination therapy in comparison with PP242 alone through fluorescence-activated cell sorting. The growth of cancer stem-like cell spheres in vitro was also maximally inhibited by combination therapy, in terms of either diameter or number. More importantly, the efficacy of combination therapy was more prominent than either drug alone in established tumor xenografts. These findings supported the potential use of combination therapy of PP242 and cetuximab against wild-type KRAS colorectal carcinomas.
authors.affiliation: Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Zuguang
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bian
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Guangchao
authors.initials: G
authors.lastname: Li
authors.affiliation: Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Biological Science and Technology and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qian
keywords: anti-EGFR treatment; cancer stem-like cells; colorectal cancer