Reference Detail

Ref Type

Journal Article

PMID

(37182602)

Authors

Elkrief A, Odintsov I, Markov V, Caeser R, Sobczuk P, Tischfield SE, Bhanot U, Vanderbilt CM, Cheng EH, Drilon A, Riely GJ, Lockwood WW, de Stanchina E, Tirunagaru VG, Doebele RC, Quintanal-Villalonga Á, Rudin CM, Somwar R, Ladanyi M

Title

Combination Therapy With MDM2 and MEK Inhibitors Is Effective in Patient-Derived Models of Lung Adenocarcinoma With Concurrent Oncogenic Drivers and MDM2 Amplification.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer			2023 May 13		J Thorac Oncol

URL

Abstract Text

Although targeted therapies have revolutionized the therapeutic landscape of lung adenocarcinomas (LUADs), disease progression on single-agent targeted therapy against known oncogenic drivers is common, and therapeutic options after disease progression are limited. In patients with MDM2 amplification (MDM2amp) and a concurrent oncogenic driver alteration, we hypothesized that targeting of the tumor-suppressor pathway (by means of restoration of p53 using MDM2 inhibition) and simultaneous targeting of co-occurring MAPK oncogenic pathway might represent a more durably effective therapeutic strategy.We evaluated genomic next-generation sequencing data using the Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets platform to nominate potential targets for combination therapy in LUAD. We investigated the small molecule MDM2 inhibitor milademetan in cell lines and patient-derived xenografts of LUAD with a known driver alteration and MDM2amp. Of 10,587 patient samples from 7121 patients with LUAD profiled by next-generation sequencing, 6% (410 of 7121) harbored MDM2amp. MDM2amp was significantly enriched among tumors with driver alterations in METex14 (36%, p < 0.001), EGFR (8%, p < 0.001), RET (12%, p < 0.01), and ALK (10%, p < 0.01). The combination of milademetan and the MEK inhibitor trametinib was synergistic in growth inhibition of ECLC5-GLx (TRIM33-RET/MDM2amp), LUAD12c (METex14/KRAS G12S /MDM2amp), SW1573 (KRAS G12C , TP53 wild type), and A549 (KRAS G12S ) cells and in increasing expression of proapoptotic proteins PUMA and BIM. Treatment of ECLC5-GLx and LUAD12c with single-agent milademetan increased ERK phosphorylation, consistent with previous data on ERK activation with MDM2 inhibition. This ERK activation was effectively suppressed by concomitant administration of trametinib. In contrast, ERK phosphorylation induced by milademetan was not suppressed by concurrent RET inhibition using selpercatinib (in ECLC5-GLx) or MET inhibition using capmatinib (in LUAD12c). In vivo, combination milademetan and trametinib was more effective than either agent alone in ECLC5-GLx, LX-285 (EGFRex19del/MDM2amp), L13BS1 (METex14/MDM2amp), and A549 (KRAS G12S , TP53 wild type). Combined MDM2/MEK inhibition was found to have efficacy across multiple patient-derived LUAD models harboring MDM2amp and concurrent oncogenic drivers. This combination, potentially applicable to LUADs with a wide variety of oncogenic driver mutations and kinase fusions activating the MAPK pathway, has evident clinical implications and will be investigated as part of a planned phase 1/2 clinical trial.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK MDM2 amp TP53 wild-type	lung adenocarcinoma	sensitive	Milademetan + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Milademetan resulted in increased tumor growth inhibition compared to either therapy alone in a patient-derived xenograft model of lung adenocarcinoma harboring wild-type TP53, EML4-ALK, and MDM2 amplification (PMID: 37182602).	37182602
BRAF G469A MDM2 amp TP53 wild-type	lung adenocarcinoma	sensitive	Milademetan + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Milademetan synergistically inhibited proliferation in a lung adenocarcinoma cell line harboring BRAF G469A with wild-type TP53 and MDM2 amplification in culture (PMID: 37182602).	37182602