Notably, the T790M-harboring cells described here are distinct from the recently described subpopulation of EGFR-mutant cancer cells lacking T790M that transiently exhibit a distinct phenotype characterized by the engagement of insulin-like growth factor 1 receptor (IGF-1R) activity, hypersensitivity to histone deacetylase (HDAC) inhibition, altered chromatin, and an intrinsic ability to tolerate drug exposure (23).
这段貌似说的是本文描述的对E(erlotinib)/B(BIBIW2992)产生耐药的细胞仅限于长时暴露在TKI之后发生T790M突变的 后面一句对其他耐药细胞系的描述确实没有看明白 所谓的"an intrinsic ability to tolerate drug exposure"又是指的哪种呢?
有几篇引用的论文感觉还挺有帮助的:
"The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP" (PDF) 详细阐述了T790M突变引起EGFR对ATP结合性增强导致的耐药性发生机理
"The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor" (html) T790M导致EGFR对低浓度不可逆TKI发生的耐药性的研究 有助于阐述为什么2992在E/G耐药之后只能维持较短的时间
继续研究这篇论文
今天又捡起这篇paper看了一下 对这段比较感兴趣:
By contrast, H3255 (L858R) cells, which also acquired T790M in response to continuous TKI exposure, neither regained TKI sensitivity nor lost the T790M after multiple passages in the absence of inhibitor, and they grew at the same rate as the parental line (fig. S3).
不知道有没有其他数据可以进一步支持L858R比Del 19更难恢复对TKI的敏感程度
Fig. 4D
(D) Patients receiving first-line erlotinib as part of a phase II trial. Four of 14 patients (28%; patients B, C, D, and H) were continued on treatment with single-agent TKI (erlotinib or gefitinib) for >6 months after RECIST progression. Asterisk denotes the presence of T790M.