First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Biomarkers, Tumor
Breast Neoplasms
/ drug therapy
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Cell Proliferation
/ drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Synergism
Female
Humans
Mice
Mitosis
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins
/ antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2
/ antagonists & inhibitors
Tumor Suppressor Protein p53
/ genetics
Xenograft Model Antitumor Assays
Breast cancer
Chemotherapy
MDM2 inhibitor
MDM4 inhibitor
p53
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
04 03 2021
04 03 2021
Historique:
received:
24
08
2020
accepted:
17
02
2021
entrez:
5
3
2021
pubmed:
6
3
2021
medline:
7
1
2022
Statut:
epublish
Résumé
MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel. ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent. The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.
Sections du résumé
BACKGROUND
MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models.
METHODS
Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel.
RESULTS
ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent.
CONCLUSION
The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.
Identifiants
pubmed: 33663585
doi: 10.1186/s13058-021-01406-x
pii: 10.1186/s13058-021-01406-x
pmc: PMC7934277
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
Cell Cycle Proteins
0
MDM4 protein, human
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins
0
Tumor Suppressor Protein p53
0
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
29Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR003167
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : Center for Clinical and Translational Sciences
ID : 12713238
Organisme : NCI NIH HHS
ID : R50 CA221675
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009599
Pays : United States
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