Combination Therapy With MDM2 and MEK Inhibitors Is Effective in Patient-Derived Models of Lung Adenocarcinoma With Concurrent Oncogenic Drivers and MDM2 Amplification.
Combination Therapy With MDM2 and MEK Inhibitors Is Effective in Patient-Derived Models of Lung Adenocarcinoma With Concurrent Oncogenic Drivers and MDM2 Amplification.
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MDM2 和 MEK 抑制剂的联合治疗对于同时具有致癌驱动因素和 MDM2 扩增的患者衍生肺腺癌模型有效。
DOI：
10.1016/j.jtho.2023.05.007
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发表时间：
2023
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作者：
Elkrief,Arielle;Odintsov,Igor;Markov,Vladimir;Caeser,Rebecca;Sobczuk,Pawel;Tischfield,SamE;Bhanot,Umesh;Vanderbilt,ChadM;Cheng,EmilyH;Drilon,Alexander;Riely,GregoryJ;Lockwood,WilliamW;deStanchina,Elisa;Tirunagaru,VijayaG;
虽然靶向治疗已经彻底改变了肺腺癌（LUAD）的治疗前景，但针对已知致癌驱动因素的单药靶向治疗的疾病进展是常见的，并且疾病进展后的治疗选择有限。在MDM 2扩增（MDM 2amp）和并发致癌驱动基因改变的患者中，我们假设肿瘤抑制通路的靶向作用（通过使用MDM 2抑制恢复p53）和同时靶向共同发生的MAPK致癌通路可能代表更持久有效的治疗策略。可操作癌症靶点的综合突变分析平台，用于提名LUAD联合治疗的潜在靶点。我们研究了小分子MDM 2抑制剂米拉美坦在具有已知驱动基因改变和MDM 2amp的LUAD细胞系和患者来源的异种移植物中的作用。（7121例中的410例）携带MDM 2amp。MDM 2amp在METex 14中具有驱动改变的肿瘤中显著富集EGFR（8%，p < 0.001）、RET（12%，p <0.01）和ALK（10%，p <0.01）。米拉美坦和MEK抑制剂曲美替尼的组合在ECLC 5-GLx（TRIM 33-RET/MDM 2amp）、LUAD 12 c（METex 14/KRASG 12 S/MDM 2amp）、SW 1573（KRASG 12 C，TP 53野生型）和A549（KRASG 12 S）细胞的生长抑制中以及在增加促细胞凋亡蛋白GSMA和BIM的表达中具有协同作用。用单药米拉美坦处理ECLC 5-GLx和LUAD 12 c增加了ERK磷酸化，这与先前关于ERK激活与MDM 2抑制的数据一致。这种ERK激活被曲美替尼联合给药有效抑制。相比之下，使用selpercatinib（在ECLC 5-GLx中）或使用capmatinib（在LUAD 12 c中）抑制MET的同时RET抑制剂未抑制米拉美坦诱导的ERK磷酸化。在体内，在ECLC 5-GLx、LX-285（EGFRex 19 del/MDM 2amp）、L13 BS 1（METex 14/MDM 2amp）和A549（KRASG 12 S，TP 53野生型）中，米拉美坦和曲美替尼组合比任一单独药物更有效。这种组合可能适用于具有多种致癌驱动突变和激活MAPK通路的激酶融合的LUAD，具有明显的临床意义，将作为计划的I/II期临床试验的一部分进行研究。
IntroductionAlthough 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 withMDM2amplification (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.MethodsWe 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 andMDM2amp.ResultsOf 10,587 patient samples from 7121 patients with LUAD profiled by next-generation sequencing, 6% (410 of 7121) harboredMDM2amp.MDM2amp was significantly enriched among tumors with driver alterations inMETex14 (36%,p< 0.001),EGFR(8%,p< 0.001),RET(12%,p< 0.01), andALK(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/KRASG12S/MDM2amp), SW1573 (KRASG12C,TP53wild type), and A549 (KRASG12S) 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 (KRASG12S, TP53 wild type).ConclusionsCombined MDM2/MEK inhibition was found to have efficacy across multiple patient-derived LUAD models harboringMDM2amp 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.