Grossmann Allie, Wang Junhua, Wee Yinshen, Jacob Thomas, Rogers Aaron, Sorensen Lise, Brooks Deja, Gupta Prachi, Tay Joshua, Wilson Emily, Liu Tong, Smith Eric, Yn Vashisht, Davies Michael, McMahon Martin, Holmen Sheri, Judson-Torres Robert, Wolff Roger
Providence Cancer Institute of Oregon.
University of Utah.
Res Sq. 2025 Aug 27:rs.3.rs-7133814. doi: 10.21203/rs.3.rs-7133814/v1.
The intrinsic ability of cancer cells to evade death underpins tumorigenesis, progression, metastasis and the survival of drug-tolerant persister (DTP) cells. Herein, we discovered that when activated, the small GTPase ARF6 plays a central role in tumor survival by facilitating expression of the BRAF oncoprotein. Tumor-specific deletion caused a significant reduction in BRAF protein and MAPK signaling and prevented rapid tumor progression. In the context of targeted therapy, BRAF inhibition induced swift activation of ARF6, driving a positive feedback loop that restored MAPK-driven anti-apoptotic signaling, facilitated DTP cell survival during the early phases of treatment and contributed to drug-tolerant growth. In patient-derived melanoma cells with innate or clinically acquired resistance to MAPK inhibitors, ARF6 inhibition enhanced sensitivity to combined BRAF + MEK inhibition. Collectively, these findings elucidate an ARF6-dependent mechanism of BRAF oncoprotein synthesis that may be exploited in BRAF driven cancers as a therapeutic vulnerability.
癌细胞逃避死亡的内在能力是肿瘤发生、进展、转移以及耐药性持久性（DTP）细胞存活的基础。在此，我们发现小GTP酶ARF6在激活后，通过促进BRAF癌蛋白的表达在肿瘤存活中发挥核心作用。肿瘤特异性缺失导致BRAF蛋白和MAPK信号显著减少，并阻止了肿瘤的快速进展。在靶向治疗的背景下，BRAF抑制诱导ARF6迅速激活，驱动一个正反馈回路，恢复MAPK驱动的抗凋亡信号，在治疗早期促进DTP细胞存活，并促进耐药性生长。在对MAPK抑制剂具有先天性或临床获得性耐药的患者来源的黑色素瘤细胞中，ARF6抑制增强了对BRAF + MEK联合抑制的敏感性。总的来说，这些发现阐明了一种ARF6依赖的BRAF癌蛋白合成机制，该机制可能在BRAF驱动的癌症中作为一种治疗靶点加以利用。
