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Differential Sensitivity of Wild-Type and BRAF-Mutated Cells to Combined BRAF and Autophagy Inhibition

机译：野生型和BRAF-突变细胞组合BRAF和自噬抑制的差异敏感性

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BRAF inhibitors are insufficient monotherapies for BRAF-mutated cancer; therefore, we investigated which inhibitory pathway would yield the most effective therapeutic approach when targeted in combination with BRAF inhibition. The oncogenic BRAF inhibitor, PLX4720, increased basal autophagic flux in BRAF-mutated cells compared to wild-type (WT) BRAF cells. Interestingly, early autophagy inhibition improved the effectiveness of PLX4720 regardless of BRAF mutation, whereas late autophagy inhibition did not. Although ATG5 knockout led to PLX4720 resistance in both WT and BRAF-mutated cells, the MEK inhibitor trametinib exhibited a synergistic effect on PLX4720 sensitivity in WT BRAF cells but not in BRAF-mutated cells. Conversely, the prolonged inhibition of endoplasmic reticulum (ER) stress reduced basal autophagy in BRAF-mutated cells, thereby increasing PLX4720 sensitivity. Taken together, our results suggest that the combined inhibition of ER stress and BRAF may simultaneously suppress both pro-survival ER stress and autophagy, and may therefore be suitable for treatment of BRAF-mutated tumors whose autophagy is increased by chronic ER stress. Similarly, for WT BRAF tumors, therapies targeting MEK signaling may be a more effective treatment strategy. Together, this study presents a rational combination treatment strategy to improve the efficacy of BRAF inhibitors depending on BRAF mutation status.
机译：BRAF抑制剂是BRAF突变癌症的单医疗不足;因此，我们研究了哪些抑制途径将在与BRAF抑制结合时产生最有效的治疗方法。与野生型（WT）BRAF细胞相比，致癌BRAF抑制剂PLX4720增加了BRAF突变细胞中的基础自噬助液。有趣的是，早期的自噬抑制改善了PLX4720的有效性，无论BRAF突变如何，而晚期的自噬抑制没有。尽管ATG5敲除导致WT和BRAF突变细胞中的PLX4720电阻，但MEK抑制剂TRAMETINIB在WT BRAF细胞中对PLX4720敏感性表现出协同作用，但不在BRAF突变细胞中。相反，延长抑制内质网（ER）胁迫降低了BRAF突变细胞中的基础自噬，从而增加了PLX4720敏感性。我们的结果表明，ER应激和BRAF的合并抑制可能同时抑制促求生存的r应激和自噬，并且因此适用于治疗慢性ER应激增加的BRAF突变的肿瘤。类似地，对于WT BRAF肿瘤，靶向MEK信号传导的疗法可能是更有效的治疗策略。在一起，本研究提出了一种合理的组合治疗策略，提高BRAF抑制剂的功效，这取决于BRAF突变状态。

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