Combined MEK/MDM2 inhibition demonstrates antitumor efficacy in TP53 wild-type thyroid and colorectal cancers with MAPK alterations

• Published in: Scientific reports Vol. 12; no. 1; p. 1248
• Main Authors: Pairawan, Seyed, Akcakanat, Argun, Kopetz, Scott, Tapia, Coya, Zheng, Xiaofeng, Chen, Huiqin, Ha, Min Jin, Rizvi, Yasmeen, Holla, Vijaykumar, Wang, Jing, Evans, Kurt W., Zhao, Ming, Busaidy, Naifa, Fang, Bingliang, Roth, Jack A., Dumbrava, Ecaterina Ileana, Meric-Bernstam, Funda
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-01-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1059/602; 631/67/1459/1843; 631/67/1504/1885; Animals; Antineoplastic Combined Chemotherapy Protocols; Antitumor activity; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Caspase-3; Cell proliferation; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Drug therapy; Female; HCT116 Cells; Humanities and Social Sciences; Humans; Immunoblotting; Immunohistochemistry; Kinases; MAP kinase; MAP Kinase Signaling System - drug effects; MDM2 protein; MEK inhibitors; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; multidisciplinary; p53 Protein; Papillary thyroid carcinoma; Protein arrays; Protein kinase; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Science; Science (multidisciplinary); Thyroid; Thyroid cancer; Thyroid Cancer, Papillary - drug therapy; Thyroid Neoplasms - drug therapy; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-05193-z

Most tumors with activating MAPK (mitogen-activated protein kinase) pathway alterations respond poorly to MEK inhibitors alone. Here, we evaluated combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 in
TP53
wild-type and MAPK altered colon and thyroid cancer models. In vitro, we showed synergy between selumetinib and KRT-232 on cell proliferation and colony formation assays. Immunoblotting confirmed p53 upregulation and MEK pathway inhibition. The combination was tested in vivo in seven patient-derived xenograft (PDX) models (five colorectal carcinoma and two papillary thyroid carcinoma models) with different
KRAS
,
BRAF
, and
NRAS
mutations. Combination therapy significantly prolonged event-free survival compared with monotherapy in six of seven models tested. Reverse-phase protein arrays and immunohistochemistry, respectively, demonstrated upregulation of the p53 pathway and in two models cleaved caspase 3 with combination therapy. In summary, combined inhibition of MEK and MDM2 upregulated p53 expression, inhibited MAPK signaling and demonstrated greater antitumor efficacy than single drug therapy in both in vitro and in vivo settings. These findings support further clinical testing of the MEK/MDM2 inhibitor combination in tumors of epithelial origin with MAPK pathway alterations.