Abstract 2218: MET alterations are enriched in lung adenocarcinoma brain metastases and define a distinct molecular and transcriptomic subtype
Authors: Burns Timothy F. , Dacic Sanja , Velez Maria A. , Somasundaram Ashwin , Bhattacharya Saveri , Chakka Anish , Yochum Zachary A. , Jin Jingxiao , Miller Ethan , Kurland Brenda F. , Bao Riyue , Normolle Danielle P. , Agnihotri Sameer , Chandran Uma R. , Stabile Laura P. 
Published: July 2021

Abstract
Lung cancer has the highest incidence of metastases to the brain, with up to 40% of non-small cell lung cancer (NSCLC) patients developing brain metastases (BM). There is a critical need to develop novel treatments to effectively prevent and treat NSCLC BM. MET is a receptor tyrosine kinase that upon binding hepatocyte growth factor (HGF), mediates proliferation, epithelial-mesenchymal transition (EMT), invasion, angiogenesis and metastasis. Recent studies have suggested that the MET pathway may be a significant determinant of metastatic potential to the brain. We evaluated 125 lung adenocarcinoma (LUAD) BM and 477 primary LUAD for MET amplification (amp) by FISH (MET/CEP &gt; 2) as well as other molecular alterations using targeted next-generation sequencing in a subset of LUAD BM (N=74) and primary LUAD (N=171) samples, including 13 paired primary and brain sets. We identified a significant enrichment of MET amp in LUAD BM (19%) compared to primary LUAD (3%; p&lt;0.00001) or liver metastases (4%, N=80; p=0.002). High MET amp (MET/CEP7 ratio &gt;5) was present in 6.5% of BM compared to 1.3% of primary LUAD cases (p=0.0006). In matched samples, BM-specific MET amp was observed. Non-exon 14 skipping MET activating mutations were also significantly more frequent in LUAD BM (22%) compared to primary LUAD (12%; p=0.05), as well as TP53, KRAS, SMAD4, APC, RB1, RET, ABL1, ALK, and VHL variants (adj. p values &lt;0.02). VHL and IDH1 mutations were significantly increased in MET altered compared to non-MET altered BM. In addition, KRAS Q61X variants were more common in LUAD BM compared to LUAD and specifically more common in MET amp BM. We also examined MET activation in paired tumors using an HGF-MET proximity binding, dual-antibody assay. MET expression was increased in the majority of BM compared to the paired LUAD, and there were brain-specific MET activation was observed. RNASeq analysis identified distinct gene signatures in MET amplified (N=11) versus non-MET amplified (N=24) LUAD BM, including upregulation of the EMT and glycolytic pathways. We validated the importance of the EMT transcription factor, TWIST1 in MET-driven NSCLC tumorigenesis preclinically and confirmed activation of the glycolytic pathway in MET amplified NSCLC. Finally, non-invasive strategies to detect brain-specific MET alterations will be needed to identify BM patients who can benefit from MET inhibitors. Therefore, we examined 277 metastatic NSCLC patients that underwent standard of care circulating tumor DNA testing with the Guardant360 platform, and found that both MET mutation and/or amp were more frequently detected in LUAD patients with BM (p=0.04). Together, we show that over a third of LUAD BM patients have MET alterations compared to primary LUAD and may be responsive to MET inhibitors. Further, our liquid biopsy approach may allow us to identify BM-specific alterations for patient selection in clinical trials.
Citation Format: Timothy F. Burns, Sanja Dacic, Maria A. Velez, Ashwin Somasundaram, Saveri Bhattacharya, Anish Chakka, Zachary A. Yochum, Jingxiao Jin, Ethan Miller, Brenda F. Kurland, Riyue Bao, Danielle P. Normolle, Sameer Agnihotri, Uma R. Chandran, Laura P. Stabile. MET alterations are enriched in lung adenocarcinoma brain metastases and define a distinct molecular and transcriptomic subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2218.