Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistance

Jianyu Peng; Zijun Lin; Weichun Chen; Jie Ruan; Fan Deng; Lin Yao; Minla Rao; Xingdong Xiong; Shun Xu; Xiangning Zhang; Xinguang Liu; Xuerong Sun

doi:10.1016/j.heliyon.2023.e17714

Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistance

Heliyon. 2023 Jul 3;9(7):e17714. doi: 10.1016/j.heliyon.2023.e17714. eCollection 2023 Jul.

Authors

Jianyu Peng^{1

2

3}, Zijun Lin^{1

2}, Weichun Chen^{1

2}, Jie Ruan², Fan Deng⁴, Lin Yao^{1

2}, Minla Rao^{1

2}, Xingdong Xiong^{1

2}, Shun Xu^{1

2}, Xiangning Zhang⁵, Xinguang Liu^{1

2}, Xuerong Sun^{1

2}

Affiliations

¹ Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China.
² Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, China.
³ Department of Laboratory Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510378, China.
⁴ Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
⁵ Department of Pathophysiology, Chinese-American Tumor Institute, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, 523808, China.

Abstract

More than one half melanoma patients have BRAF gene mutation. BRAF inhibitor vemurafenib is an effective medication for these patients. However, acquired resistance is generally inevitable, the mechanisms of which are not fully understood. Cell senescence and senescence-associated secretory phenotype (SASP) are involved in extensive biological functions. This study was designed to explore the possible role of senescent cells in vemurafenib resistance. The results showed that vemurafenib treatment induced BRAF-mutant but not wild-type melanoma cells into senescence, as manifested by positive β-galactosidase staining, cell cycle arrest, enlarged cellular morphology, and cyclin D1/p-Rb pathway inhibition. However, the senescent cells induced by vemurafenib (SenV) did not display DNA damage response, p53/p21 pathway activation, reactive oxygen species accumulation, decline of mitochondrial membrane potential, or secretion of canonical SASP cytokines. Instead, SenV released other cytokines, including CCL2, TIMP2, and NGFR, to protect normal melanoma cells from growth inhibition upon vemurafenib treatment. Xenograft experiments further confirmed that vemurafenib induced melanoma cells into senescence in vivo. The results suggest that vemurafenib can induce robust senescence in BRAF^V600E melanoma cells, leading to the release of resistance-conferring cytokines. Both the senescent cells and the resistant cytokines could be potential targets for tackling vemurafenib resistance.

Keywords: BRAF inhibitors; Cell senescence; Cytokines; Melanoma; Resistance; Vemurafenib.