Li Ye, Yuan Yuncang, Zhang Fan, Guo Aizhen, Cao Fuao, Song Mengmeng, Fu Yating, Xu Xiaowen, Shen Hao, Zheng Shangyong, Pan Yamin, Chang Wenjun
Department of Digestive Endoscopy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Environmental and Occupational Health, Second Military Medical University, Shanghai, China.
Front Pharmacol. 2021 Nov 1;12:739501. doi: 10.3389/fphar.2021.739501. eCollection 2021.
SHP2 mediates signaling from multiple receptor tyrosine kinases (RTKs) to extracellular signal-regulated kinase (ERK) and Ser and Thr kinase AKT, and its inhibitors offer an unprecedented opportunity for cancer treatment. Although the ERK signaling variation after SHP2 inhibition has been well investigated, the AKT signaling variation in colorectal carcinoma (CRC) is still unknown. Therefore, we performed immunohistochemistry and bioinformatics analyses to explore the significance of p-SHP2 in CRC. A panel of CRC cell lines with the SHP2 inhibitor, SHP099, was used to assess the effects on viability and signaling. The inhibitors of AKT and focal adhesion kinase (FAK) signaling were examined in combination with SHP099 as potential strategies to enhance the efficacy and overcome resistance. Frequent resistance to the SHP2 inhibitor was observed in CRC cells, even in those without RAS mutations. We observed rapid adaptive reactivation of the AKT pathway in response to SHP2 inhibition, possibly driven by the reactivation of RTKs or released -FAK. High baseline p-FAK may also be associated with CRC cell resistance to SHP2 inhibition. Co-inhibition of FAK abrogated the feedback reactivation of AKT in response to SHP2 inhibition. Moreover, the combined inhibition of SHP2 with AKT or FAK resulted in sustained AKT pathway suppression and improved antitumor efficacy and . Our study found that reactivation of the AKT pathway is a key mechanism of adaptive resistance to SHP2 inhibition, highlighting the potential significance of AKT and FAK inhibition strategies to enhance the efficacy of SHP2 inhibitors in CRC treatment.
SHP2介导从多种受体酪氨酸激酶（RTK）到细胞外信号调节激酶（ERK）以及丝氨酸和苏氨酸激酶AKT的信号传导，其抑制剂为癌症治疗提供了前所未有的机会。尽管SHP2抑制后ERK信号变化已得到充分研究，但结直肠癌（CRC）中AKT信号变化仍不清楚。因此，我们进行了免疫组织化学和生物信息学分析，以探讨p-SHP2在CRC中的意义。使用一组含有SHP2抑制剂SHP099的CRC细胞系来评估对活力和信号传导的影响。研究了将AKT和粘着斑激酶（FAK）信号抑制剂与SHP099联合使用，作为增强疗效和克服耐药性的潜在策略。在CRC细胞中观察到对SHP2抑制剂频繁耐药，即使在没有RAS突变的细胞中也是如此。我们观察到，响应SHP2抑制，AKT途径会迅速发生适应性重新激活，这可能是由RTK重新激活或释放的-FAK驱动的。高基线p-FAK也可能与CRC细胞对SHP2抑制的耐药性有关。FAK的共同抑制消除了响应SHP2抑制时AKT的反馈性重新激活。此外，SHP2与AKT或FAK的联合抑制导致AKT途径持续受到抑制，并提高了抗肿瘤疗效。我们的研究发现，AKT途径的重新激活是对SHP2抑制产生适应性耐药的关键机制，突出了AKT和FAK抑制策略在增强SHP2抑制剂治疗CRC疗效方面的潜在意义。
