河马信号通路及其下游效应物质YAP在细胞增殖中起着核心作用。河马通路的失调会触发YAP过度活化，从而诱导头颈鳞状细胞癌（HNSCC）的发生。最近，我们报告说EGFR促进了MOB1的酪氨酸磷酸化及其后的LATS1/2失活，这些都是河马通路的核心成分，导致YAP被激活。然而，EGFR单一靶向治疗在HNSCC患者中表现出较低的反应率。鉴于YAP在对EGFR靶向治疗有抗药性的患者样本中被激活，EGFR抑制剂可能暂时使YAP失活，但YAP的本质过活化或再次激活可能导致其对EGFR抑制剂在HNSCC细胞中的抗药性。YAP在对EGFR抑制剂产生抗药性的HNSCC中的激活机制尚不清楚。全面的转录分析揭示了AXL通过一种新的机制激活YAP：AXL与EGFR异二聚体形成，从而通过EGFR-LATS1/2轴激活YAP。AXL和EGFR抑制剂的联合治疗能够协同地使YAP失活，并抑制HNSCC和肺腺癌细胞的生存能力。相反，LATS1/2基因缺失和YAP过度活化使得这些抑制剂的协同效应受到了抵抗。我们的发现表明，同时靶向AXL和EGFR是治疗EGFR变异癌症患者的一种有前景的治疗方法。©2023.作者（们），在SpringerNatureLimited独家许可下发表。

The Hippo signaling pathway and its downstream effector YAP play a central role in cell proliferation. Dysregulation of the Hippo pathway triggers YAP hyperactivation, thereby inducing head and neck squamous cell carcinoma (HNSCC). Recently, we reported that EGFR promotes tyrosine phosphorylation of MOB1 and subsequent LATS1/2 inactivation, which are core components of the Hippo pathway, resulting in YAP activation. However, EGFR-targeted monotherapy has shown a low response rate in HNSCC patients. Given that YAP is activated in patient samples refractory to EGFR-targeted therapy, EGFR inhibitors may temporarily inactivate YAP, but intrinsic hyperactivation or acquired reactivation of YAP may confer resistance to EGFR inhibitors in HNSCC cells. The mechanism by which YAP is activated in HNSCC resistant to EGFR inhibitors remains unclear. Comprehensive transcriptional analysis revealed that AXL activates YAP through a novel mechanism: AXL heterodimerizes with EGFR, thereby activating YAP via the EGFR-LATS1/2 axis. The combination of AXL and EGFR inhibitors synergistically inactivates YAP and suppresses the viability of HNSCC and lung adenocarcinoma cells. In turn, LATS1/2 knockout and YAP hyperactivation confer resistance to the synergistic effects of these inhibitors. Our findings suggest that co-targeting both AXL and EGFR represent a promising therapeutic approach in patients with EGFR-altered cancers.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.