Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer.
Animals
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Drug Evaluation, Preclinical
/ methods
Drug Resistance, Neoplasm
/ drug effects
Female
Humans
Lapatinib
/ pharmacology
Mice
Mice, Inbred BALB C
Mice, Nude
Phosphatidylinositol 3-Kinases
/ metabolism
Protein Kinase Inhibitors
/ pharmacology
Protein Serine-Threonine Kinases
/ metabolism
Pyridines
/ pharmacology
Pyrimidines
/ pharmacology
Signal Transduction
/ drug effects
TOR Serine-Threonine Kinases
/ metabolism
Thiophenes
/ pharmacology
Trastuzumab
/ pharmacology
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
28
03
2019
accepted:
30
01
2020
revised:
20
01
2020
pubmed:
12
2
2020
medline:
21
11
2020
entrez:
12
2
2020
Statut:
ppublish
Résumé
The proviral integration of Moloney virus (PIM) family of protein kinases are overexpressed in many haematological and solid tumours. PIM kinase expression is elevated in PI3K inhibitor-treated breast cancer samples, suggesting a major resistance pathway for PI3K inhibitors in breast cancer, potentially limiting their clinical utility. IBL-302 is a novel molecule that inhibits both PIM and PI3K/AKT/mTOR signalling. We thus evaluated the preclinical activity of IBL-302, in a range of breast cancer models. Our results demonstrate in vitro efficacy of IBL-302 in a range of breast cancer cell lines, including lines with acquired resistance to trastuzumab and lapatinib. IBL-302 demonstrated single-agent, anti-tumour efficacy in suppression of pAKT, pmTOR and pBAD in the SKBR-3, BT-474 and HCC-1954 HER2+/PIK3CA-mutated cell lines. We have also shown the in vivo single-agent efficacy of IBL-302 in the subcutaneous BT-474 and HCC-1954 xenograft model in BALB/c nude mice. The combination of trastuzumab and IBL-302 significantly increased the anti-proliferative effect in HER2+ breast cancer cell line, and matched trastuzumab-resistant line, relative to testing either drug alone. We thus believe that the novel PIM and PI3K/mTOR inhibitor, IBL-302, represents an exciting new potential treatment option for breast cancer, and that it should be considered for clinical investigation.
Identifiants
pubmed: 32042115
doi: 10.1038/s41388-020-1202-y
pii: 10.1038/s41388-020-1202-y
pmc: PMC7118022
doi:
Substances chimiques
IBL-302
0
Protein Kinase Inhibitors
0
Pyridines
0
Pyrimidines
0
Thiophenes
0
Lapatinib
0VUA21238F
MTOR protein, human
EC 2.7.1.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Trastuzumab
P188ANX8CK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3028-3040Références
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