A destabilizing Y891D mutation in activated EGFR impairs sensitivity to kinase inhibition.
A destabilizing Y891D mutation in activated EGFR impairs sensitivity to kinase inhibition.
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激活的EGFR中一个不稳定的Y891D突变会削弱对激酶抑制的敏感性。
DOI：
10.1038/s41698-023-00490-w
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发表时间：
2024-01-05
影响因子：
7.9
通讯作者：
中科院分区：
文献类型：
--
作者：
EGFR酪氨酸激酶抑制剂（TKI）已经改变了EGFR突变型非小细胞肺癌（NSCLC）的治疗;然而，治疗耐药性仍然是一个临床挑战。增加ATP亲和力和/或损害抑制剂结合的获得性继发性EGFR突变是充分描述的耐药介质。在此，我们确定了EGFR L 858 R的NSCLC中新发EGFR Y891 D继发性改变。既往报告获得性EGFR Y891 D改变与第一代EGFR TKI耐药相关。Ba/F3细胞中的功能研究表明EGFR L 858 R + Y891 D的TKI敏感性降低，第一代和第二代TKI的降低幅度最大。与其他与TKI耐药相关的EGFR突变不同，Y891 D不会显著改变ATP亲和力或促进抑制剂结合的空间位阻。我们的数据表明，Y891 D突变使EGFR L 858 R不稳定，可能产生一群错误折叠的受体，保留了信号传导能力，但对EGFR抑制剂的敏感性降低。这些发现提高了蛋白质错误折叠作为EGFR突变NSCLC中EGFR抑制耐药机制的可能性。
EGFR tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutated non-small cell lung carcinoma (NSCLC); however, therapeutic resistance remains a clinical challenge. Acquired secondary EGFR mutations that increase ATP affinity and/or impair inhibitor binding are well-described mediators of resistance. Here we identify a de novo EGFR Y891D secondary alteration in a NSCLC with EGFR L858R. Acquired EGFR Y891D alterations were previously reported in association with resistance to first generation EGFR TKIs. Functional studies in Ba/F3 cells demonstrate reduced TKI sensitivity of EGFR L858R + Y891D, with the greatest reduction observed for first and second generation TKIs. Unlike other EGFR mutations associated with TKI resistance, Y891D does not significantly alter ATP affinity or promote steric hindrance to inhibitor binding. Our data suggest that the Y891D mutation destabilizes EGFR L858R, potentially generating a population of misfolded receptor with preserved signaling capacity but reduced sensitivity to EGFR inhibitors. These findings raise the possibility of protein misfolding as a mechanism of resistance to EGFR inhibition in EGFR-mutated NSCLC.
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