Combination of MDM2 and targeted kinase inhibitors results in prolonged tumor control in lung adenocarcinomas with oncogenic tyrosine kinase drivers and MDM2 amplification Journal Article


Authors: Elkrief, A.; Odintsov, I.; Smith, R. S.; Vojnic, M.; Hayashi, T.; Khodos, I.; Markov, V.; Liu, Z.; Lui, A. J. W.; Bloom, J. L.; Offin, M. D.; Rudin, C. M.; de Stanchina, E.; Riely, G. J.; Somwar, R.; Ladanyi, M.
Article Title: Combination of MDM2 and targeted kinase inhibitors results in prolonged tumor control in lung adenocarcinomas with oncogenic tyrosine kinase drivers and MDM2 amplification
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.
Keywords: solid tumors; resistance; therapies; open-label; platform; cancer; 1st-in-human; milademetan
Journal Title: JCO Precision Oncology
Volume: 8
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2024-10-01
Language: English
ACCESSION: WOS:001315703100004
DOI: 10.1200/po.24.00241
PROVIDER: wos
PMCID: PMC11404768
PUBMED: 39259915
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Marc Ladanyi -- Source: Wos
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MSK Authors
  1. Marc Ladanyi
    1332 Ladanyi
  2. Gregory J Riely
    604 Riely
  3. Romel Somwar
    111 Somwar
  4. Charles Rudin
    495 Rudin
  5. Roger Stephen Smith
    20 Smith
  6. Inna   Khodos
    36 Khodos
  7. Michael David Offin
    172 Offin
  8. Morana Vojnic
    17 Vojnic
  9. Jo Weng Allan Lui
    15 Lui
  10. Zebing Liu
    5 Liu
  11. Arielle Elkrief
    43 Elkrief
  12. Vladimir Aleksandrov Markov
    6 Markov
  13. Jamie Lawrence Bloom
    1 Bloom