Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. Many lung cancer patients will develop resistance to chemotherapeutics. In the context of non-small cell lung cancers harboring EGFR oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive Erlotinib resistance in certain tumors with mesenchymal-like features. By studying the ontogeny of AXL-positive cells, we have identified a novel non-genetic mechanism of drug resistance based on cell-state transition. We demonstrate that AXL-positive cells are already present as a sub-population of cancer cells in Erlotinib-naïve tumors and tumor-derived cell lines, and that the expression of AXL is regulated through a stochastic mechanism centered on the epigenetic regulation of miR-335. The existence of a cell-intrinsic program through which AXL-positive/Erlotinib-resistant cells emerge infers the need of treating tumors harboring EGFR oncogenic mutations upfront with combinatorial treatments targeting both AXL-negative and AXL-positive cancer cells.

中文翻译：

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表观遗传开关通过调节miR-335的表达来调节AXL阳性/ EGFR-TKI耐药细胞的个体发育

尽管目前在研究和治疗方面取得了进步，但是肺癌仍然是全世界与癌症相关的死亡率的主要原因。许多肺癌患者会对化学治疗产生抵抗力。在具有EGFR致癌突变的非小细胞肺癌的背景下，已发现AXL和GAS6的水平升高会在某些具有间充质样特征的肿瘤中驱动埃洛替尼耐药。通过研究AXL阳性细胞的个体发育，我们已经确定了基于细胞状态转变的新型非遗传耐药性机制。我们证明AXL阳性细胞已经作为未分化的厄洛替尼（elotlotib）肿瘤和肿瘤衍生细胞系中的癌细胞亚群存在，并且AXL的表达通过以miR-的表观遗传调控为中心的随机机制进行调控335。