Data from Germline <i>USP36</i> Mutation Confers Resistance to EGFR-TKIs by Upregulating MLLT3 Expression in Patients with Non–Small Cell Lung Cancer

• DOI: 10.1158/1078-0432.c.7158238.v1
• Publication Date: 2024-04-01T07:24:37Z
• Authors: Shaoxing Guan; Xi Chen; Yuru Wei; Fei Wang; Wen Xie; Youhao Chen; Heng Liang; Xia Zhu; Yunpeng Yang; Wenfeng Fang; Yan Huang; Hongyun Zhao; Xiaoxu Zhang; Shu Liu; Wei Zhuang; Min Huang; Xueding Wang; Li Zhang

&lt;div&gt;AbstractPurpose:&lt;p&gt;Although somatic mutations were explored in depth, limited biomarkers found to predict the resistance of EGFR tyrosine kinase inhibitors (EGFR-TKI). Previous studies reported N6-methyladenosine (m6A) levels regulated response EGFR-TKIs; whether germline variants located m6A sites affected EGFR-TKIs is still unknown.&lt;/p&gt;Experimental Design:&lt;p&gt;Patients with non–small cell lung cancer (NSCLC) EGFR-activating mutation enrolled investigate predictors for using a genome-wide-variant-m6A analysis. Bioinformatics analysis and series molecular biology assays used uncover underlying mechanism.&lt;/p&gt;Results:&lt;p&gt;We identified &lt;i&gt;USP36&lt;/i&gt; rs3744797 (C &gt; A, K814N) was associated survival patients NSCLC treated gefitinib [median progression-free (PFS): CC vs. CA, 16.30 10.50 months, &lt;i&gt;P&lt;/i&gt; &lt; 0.0001, HR = 2.45] erlotinib (median PFS: 14.13 9.47 0.041, 2.63). Functionally, C A change significantly upregulated USP36 expression by reducing its level. Meanwhile, rs3744797_A (&lt;i&gt;USP36&lt;/i&gt; MUT) facilitate proliferation, migration, via upregulating MLLT3 &lt;i&gt;in vitro&lt;/i&gt; vivo&lt;/i&gt;. More importantly, are tightly correlated NSCLC, which prognosis patients. Mechanistically, MUT stabilized deubiquitinating nucleoli consequently activating downstream signaling (HIF1α Snai). Furthermore, inhibition alleviated variant–induced EGFR-mutant NSCLC.&lt;/p&gt;Conclusions:&lt;p&gt;These findings characterized as an oncogenic variant mediating EGFR-TKI tumor aggressiveness through MLLT3, highlighting predictive biomarker NSCLC.&lt;/p&gt;&lt;/div&gt;