PMID- 34532116
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220426
IS  - 2078-6891 (Print)
IS  - 2219-679X (Electronic)
IS  - 2078-6891 (Linking)
VI  - 12
IP  - 4
DP  - 2021 Aug
TI  - A dual-targeted molecular therapy of PP242 and cetuximab plays an anti-tumor 
      effect through EGFR downstream signaling pathways in colorectal cancer.
PG  - 1625-1642
LID - 10.21037/jgo-21-467 [doi]
AB  - BACKGROUND: Epidermal growth factor receptor (EGFR) and its downstream 
      Ras-mitogen-activated protein kinase kinase (MAPKK, MEK)-extracellular regulated 
      protein kinase (ERK) signaling pathway and phosphatidylinositol 3-kinase 
      (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling 
      pathway play important roles in the pathogenesis of colorectal cancer (CRC). The 
      combination therapy of anti-EGFR and anti-mTOR needs to be explored. METHODS: 
      Here we combined the anti-EGFR monoclonal antibody cetuximab (CTX) with the mTOR 
      inhibitor PP242 in CRC cell lines and mouse xenograft models and discussed the 
      changes of EGFR downstream signaling pathways of CRC cell lines. RESULTS: In 
      HT-29 cells and Caco-2 cells, combined application of CTX and PP242 significantly 
      inhibited the proliferation of CRC cells in vivo and in vitro. In BRAF wild-type 
      Caco-2 cells, combined application of CTX and PP242 inhibited the activation of 
      the EGFR and its downstream signaling pathways. CONCLUSIONS: Our research further 
      demonstrates the effectiveness of the combined application of CTX and PP242 in 
      inhibiting CRC cell lines from the perspective of cell proliferation, cell cycle, 
      apoptosis, and mouse xenografts. We revealed that the combined application of CTX 
      and PP242 can inhibit tumor growth and proliferation by inhibiting the 
      phosphorylation of key molecules in EGFR downstream MEK-ERK and MEK 4/7 
      (MKK)-c-Jun N-terminal kinase (JNK) signaling pathways in BRAF wild-type CRC 
      cells. In addition, we found that in BRAF mutant CRC cells, the monotherapy of 
      PP242 resulted in negative feedback increased EGFR phosphorylation rates, 
      accompanied by significant up-regulation of downstream MEK and ERK 
      phosphorylation.
CI  - 2021 Journal of Gastrointestinal Oncology. All rights reserved.
FAU - Kong, Linghui
AU  - Kong L
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated 
      Hospital of Nanjing University Medical School, Nanjing, China.
FAU - Zhang, Qun
AU  - Zhang Q
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated 
      Hospital of Nanjing University Medical School, Nanjing, China.
FAU - Mao, Jialei
AU  - Mao J
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College 
      of Nanjing University of Chinese Medicine, Nanjing, China.
FAU - Cheng, Lei
AU  - Cheng L
AD  - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Shi, Xiao
AU  - Shi X
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated 
      Hospital of Nanjing University Medical School, Nanjing, China.
FAU - Yu, Lixia
AU  - Yu L
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated 
      Hospital of Nanjing University Medical School, Nanjing, China.
FAU - Hu, Jing
AU  - Hu J
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated 
      Hospital of Nanjing University Medical School, Nanjing, China.
FAU - Yang, Mi
AU  - Yang M
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated 
      Hospital of Nanjing University Medical School, Nanjing, China.
FAU - Li, Li
AU  - Li L
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated 
      Hospital of Nanjing University Medical School, Nanjing, China.
FAU - Liu, Baorui
AU  - Liu B
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated 
      Hospital of Nanjing University Medical School, Nanjing, China.
FAU - Qian, Xiaoping
AU  - Qian X
AD  - The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated 
      Hospital of Nanjing University Medical School, Nanjing, China.
LA  - eng
PT  - Journal Article
PL  - China
TA  - J Gastrointest Oncol
JT  - Journal of gastrointestinal oncology
JID - 101557751
PMC - PMC8421906
OTO - NOTNLM
OT  - Colorectal cancer (CRC)
OT  - epidermal growth factor receptor (EGFR)
OT  - mammalian target of rapamycin (mTOR)
OT  - signal transduction
OT  - targeted molecular therapy
COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure 
      form (available at https://dx.doi.org/10.21037/jgo-21-467). The authors have no 
      conflicts of interest to declare.
EDAT- 2021/09/18 06:00
MHDA- 2021/09/18 06:01
PMCR- 2021/08/01
CRDT- 2021/09/17 07:16
PHST- 2021/06/29 00:00 [received]
PHST- 2021/08/18 00:00 [accepted]
PHST- 2021/09/17 07:16 [entrez]
PHST- 2021/09/18 06:00 [pubmed]
PHST- 2021/09/18 06:01 [medline]
PHST- 2021/08/01 00:00 [pmc-release]
AID - jgo-12-04-1625 [pii]
AID - 10.21037/jgo-21-467 [doi]
PST - ppublish
SO  - J Gastrointest Oncol. 2021 Aug;12(4):1625-1642. doi: 10.21037/jgo-21-467.