2. Academic Validation
  3. Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and MDM2 Amplification

Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and MDM2 Amplification

  • JCO Precis Oncol. 2024 Sep:8:e2400241. doi: 10.1200/PO.24.00241.
Arielle Elkrief 1 2 3,  Igor Odintsov 1 2 4,  Roger S Smith 1,  Morana Vojnic 1 2,  Takuo Hayashi 1 2,  Inna Khodos 5,  Vladimir Markov 5,  Zebing Liu 1 2,  Allan J W Lui 1 2,  Jamie L Bloom 1,  Michael D Offin 3 6,  Charles M Rudin 3 6,  Elisa de Stanchina 5,  Gregory J Riely 3 6,  Romel Somwar 1 2,  Marc Ladanyi 1 2
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 2 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 3 Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 4 Department of Pathology, Brigham and Women's Hospital, Boston, MA.
  • 5 Anti-tumor Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 6 Department of Medicine, Weill Cornell, New York, NY.
PMID: 39259915 DOI: 10.1200/PO.24.00241
Abstract

Purpose: MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. MDM2 amplification (MDM2amp) is mutually exclusive with TP53 mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations. However, the combination of MDM2 and RTK inhibitors in LUAD has not been studied.

Methods: We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD.

Results: In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone.

Conclusion: These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.

Figures
Products