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
  • 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.

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