He Ying, Li Wei, Zhang Meiling, Wang Hui, Lin Peilu, Yu Ying, Huang Bin, Hao Meng, He Jianuo, Kong Weiyao, Luo Dan, Xu Tengteng, Wang Jiaqi, Huang Ying, Zhao Qinwen, Liu Ying, Zhang Jie, Nian Yong, Zhang Lei, Zhu Bo, Yin Chengqian
Institute of Cancer Research, Shenzhen Bay Laboratory , Shenzhen, China.
Medical Research Institute, Guangdong Provincial People's Hospital, Southern Medical University , Guangzhou, China.
J Exp Med. 2025 Mar 3;222(3). doi: 10.1084/jem.20241147. Epub 2025 Jan 22.
BRAF mutations drive initiation and progression of various tumors. While BRAF inhibitors are effective in BRAF-mutant melanoma patients, intrinsic or acquired resistance to these therapies is common. Here, we identify non-receptor-type protein tyrosine phosphatase 23 (PTPN23) as an alternative effective target in BRAF-mutant cancer cells. Silencing PTPN23 selectively kills BRAF-mutant melanoma cells but not those with wild-type BRAF. Mechanistically, PTPN23, a catalytically inactive phosphatase, intriguingly induces WNK3-mediated phosphorylation of phosphoinositide 3-kinase class II alpha (PI3KC2α) at serine 329, enhancing its catalytic activity. This activation promotes production of PI(3,4)P2 and subsequent AKT2 activation at endosomes to support cell survival. Genetic or pharmacological targeting of the PTPN23-PI3KC2α-AKT2 signaling axis, alone or in combination with BRAF inhibitors, effectively inhibits the growth of BRAF-mutant melanoma and other cancers in vitro and in vivo. We also demonstrate that melanocyte-specific knockout of PTPN23 significantly inhibits BRAFV600E-driven melanomagenesis. Altogether, our findings demonstrate that targeting PTPN23/PI3KC2α offers a new and viable therapeutic strategy for BRAF-mutant cancers.
BRAF突变驱动各种肿瘤的起始和进展。虽然BRAF抑制剂对BRAF突变的黑色素瘤患者有效，但对这些疗法的内在或获得性耐药很常见。在此，我们确定非受体型蛋白酪氨酸磷酸酶23（PTPN23）是BRAF突变癌细胞中的另一个有效靶点。沉默PTPN23可选择性杀死BRAF突变的黑色素瘤细胞，但不会杀死野生型BRAF的细胞。从机制上讲，PTPN23是一种无催化活性的磷酸酶，有趣的是，它能诱导WNK3介导的磷酸肌醇3激酶IIα类（PI3KC2α）在丝氨酸329处的磷酸化，增强其催化活性。这种激活促进PI(3,4)P2的产生以及随后在内体处AKT2的激活，以支持细胞存活。对PTPN23-PI3KC2α-AKT2信号轴进行基因或药理学靶向，单独或与BRAF抑制剂联合使用，可在体外和体内有效抑制BRAF突变的黑色素瘤和其他癌症的生长。我们还证明，黑色素细胞特异性敲除PTPN23可显著抑制BRAFV600E驱动的黑色素瘤发生。总之，我们的研究结果表明，靶向PTPN23/PI3KC2α为BRAF突变癌症提供了一种新的可行治疗策略。
