2023 Targeted Therapies of Lung Cancer Meeting (Poster)-P1.13. MDM2 Inhibition in Combination with MEK Inhibition in Pre-clinical Models of Lung Adenocarcinomas with MDM2 Amplification

P1.13. MDM2 Inhibition in Combination with MEK Inhibition in Pre-clinical Models of Lung Adenocarcinomas with MDM2 Amplification

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This document presents research on the combination of MDM2 and MEK inhibition as a potential treatment strategy for lung adenocarcinomas with MDM2 amplification. The study found that MDM2 amplifications are significantly enriched in patients with lung adenocarcinomas who also have driver alterations in receptor tyrosine kinases such as EGFR, RET, METex, and ALK. The authors hypothesize that combining therapies directed at a known driver alteration and MDM2 amplification could extend the effectiveness of targeted therapy in these patients. <br /><br />In vitro studies showed that MDM2 and MEK inhibition is synergistic, leading to increased apoptosis compared to either agent alone. The combination therapy also caused increased phosphorylation of ERK, which was suppressed by MEK inhibition. In vivo studies in patient-derived models of lung adenocarcinoma with MDM2 amplification and driver alterations demonstrated that the combination therapy was more effective in reducing tumor volume compared to individual agents or control. <br /><br />The study also analyzed the expression of MDM2 in patient-derived cell lines and a patient cohort with lung adenocarcinoma. The results showed an elevated expression of MDM2 in cell lines and in a subset of patients with MDM2 amplification. <br /><br />Overall, the findings suggest that combination MDM2/MEK inhibition could be an effective treatment strategy for lung adenocarcinomas with MDM2 amplification and driver alterations. The authors recommend further evaluation of this approach in clinical trials.

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Arielle Elkrief, Memorial Sloan Kettering Cancer Center, United States

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Speaker Arielle Elkrief, Memorial Sloan Kettering Cancer Center, United States

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Keywords

MDM2

MEK inhibition

lung adenocarcinomas

MDM2 amplification

driver alterations

receptor tyrosine kinases

EGFR

RET

METex

ALK