Combined blockade of MEK and PI3KCA as an effective antitumor strategy in HER2 gene amplified human colorectal cancer models.
Animals
Antineoplastic Agents
/ pharmacology
Biomarkers, Tumor
Cell Line, Tumor
Colorectal Neoplasms
/ drug therapy
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
/ drug effects
Female
Gene Amplification
Humans
MAP Kinase Kinase Kinases
/ antagonists & inhibitors
Mice
Nuclear Proteins
/ antagonists & inhibitors
Protein Kinase Inhibitors
/ pharmacology
Receptor, ErbB-2
/ genetics
Transcription Factors
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Colorectal cancer
HER2-amplified cancer
MEK and PI3KCA inhibitors; xenografts; patient-derived xenografts
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
04 Jun 2019
04 Jun 2019
Historique:
received:
06
03
2019
accepted:
13
05
2019
entrez:
6
6
2019
pubmed:
6
6
2019
medline:
26
11
2019
Statut:
epublish
Résumé
Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients receive clinical benefits from anti-EGFR therapies, due to the development of resistance mechanisms. In this regard, HER2 has emerged as an actionable target in the treatment of mCRC patients with resistance to anti-EGFR therapy. We have used SW48 and LIM1215 human colon cancer cell lines, quadruple wild-type for KRAS, NRAS, BRAF and PI3KCA genes, and their HER2-amplified (LIM1215-HER2 and SW48-HER2) derived cells to perform in vitro and in vivo studies in order to identify novel therapeutic strategies in HER2 gene amplified human colorectal cancer. LIM1215-HER2 and SW48-HER2 cells showed over-expression and activation of the HER family receptors and concomitant intracellular downstream signaling including the pro-survival PI3KCA/AKT and the mitogenic RAS/RAF/MEK/MAPK pathways. HER2-amplified cells were treated with several agents including anti-EGFR antibodies (cetuximab, SYM004 and MM151); anti-HER2 (trastuzumab, pertuzumab and lapatinib) inhibitors; anti-HER3 (duligotuzumab) inhibitors; and MEK and PI3KCA inhibitors, such as refametinib and pictilisib, as single agents and in combination. Subsequently, different in vivo experiments have been performed. MEK plus PI3KCA inhibitors treatment determined the best antitumor activity. These results were validated in vivo in HER2-amplified patient derived tumor xenografts from three metastatic colorectal cancer patients. These results suggest that combined therapy with MEK and PI3KCA inhibitors could represent a novel and effective treatment option for HER2-amplified colorectal cancer.
Sections du résumé
BACKGROUND
BACKGROUND
Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients receive clinical benefits from anti-EGFR therapies, due to the development of resistance mechanisms. In this regard, HER2 has emerged as an actionable target in the treatment of mCRC patients with resistance to anti-EGFR therapy.
METHODS
METHODS
We have used SW48 and LIM1215 human colon cancer cell lines, quadruple wild-type for KRAS, NRAS, BRAF and PI3KCA genes, and their HER2-amplified (LIM1215-HER2 and SW48-HER2) derived cells to perform in vitro and in vivo studies in order to identify novel therapeutic strategies in HER2 gene amplified human colorectal cancer.
RESULTS
RESULTS
LIM1215-HER2 and SW48-HER2 cells showed over-expression and activation of the HER family receptors and concomitant intracellular downstream signaling including the pro-survival PI3KCA/AKT and the mitogenic RAS/RAF/MEK/MAPK pathways. HER2-amplified cells were treated with several agents including anti-EGFR antibodies (cetuximab, SYM004 and MM151); anti-HER2 (trastuzumab, pertuzumab and lapatinib) inhibitors; anti-HER3 (duligotuzumab) inhibitors; and MEK and PI3KCA inhibitors, such as refametinib and pictilisib, as single agents and in combination. Subsequently, different in vivo experiments have been performed. MEK plus PI3KCA inhibitors treatment determined the best antitumor activity. These results were validated in vivo in HER2-amplified patient derived tumor xenografts from three metastatic colorectal cancer patients.
CONCLUSIONS
CONCLUSIONS
These results suggest that combined therapy with MEK and PI3KCA inhibitors could represent a novel and effective treatment option for HER2-amplified colorectal cancer.
Identifiants
pubmed: 31164152
doi: 10.1186/s13046-019-1230-z
pii: 10.1186/s13046-019-1230-z
pmc: PMC6549349
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
Nuclear Proteins
0
PI3KCA protein, human
0
Protein Kinase Inhibitors
0
Transcription Factors
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
MAP Kinase Kinase Kinases
EC 2.7.11.25
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
236Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG 18972
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