PTPN11介导了多种RTKs对AKT、ERK等信号的激活，即使在KRAS和某些BRAF突变肿瘤中，仍发挥关键作用。申请人发现结直肠癌（CRC）对PTPN11抑制剂产生耐药表型且伴随pS897-EPHA2升高；联用EPHA2和PTPN11抑制剂，则对CRC产生协同致死效应。目前，PTPN11阻断如何激活EPHA2以及为何产生上述协同致死效应，其机制尚不清楚，故本研究拟：（1）阐明PTPN11阻断导致EPHA2激活的分子机制；（2）评价PTPN11和EPHA2联合阻断对CRC的生物学功能；（3）比较PTPN11和EPHA2所干涉的下游信号，发现介导协同致死作用的关键分子；（4）评价PTPN11和EPHA2及其下游节点作为CRC预后标志的价值。本课题不仅揭示了PTPN11和EPHA2信号之间的交互关系，而且评价了PTPN11和EPHA2联合阻断在CRC中的治疗潜能，为CRC的诊治提供新思路。

PTPN11 is a member of the protein tyrosine phosphatase family which can mediate the function of multiple receptor tyrosine kinases to activate the signaling of ERK and AKT. Despite of KRAS mutation or some BRAF mutations, the inhibition of PTPN11 with SHP099 still can generate a significant effect on multiple tumor models, which have make PTPN11 as an attractive cancer target. Recently, we have found that colorectal cancer (CRC) may generate a resistance phenotype against SHP099, possibly associated with a feedback activation of EPHA2 signaling. The combined inhibitions of PTPN11 and EPHA2 signaling with their inhibitors result in the effect of synthetic inhibition. However, it is unknown how PTPN11 inhibition results in the activated EPHA2 signaling and how the combined inhibition generates the synthetic lethality? In the grant, we will investigate the underlying mechanism of the feedback activation of EPHA2 after PTPN11 inhibition, and evaluate the biological significance of the combined blocking of PTPN11 and EPHA2 on the CRC models. We also compare the differences of downstream signaling among PTPN11, EPHA2 and their combination to find out the critical nodes associated with the synthetic lethality. Finally, we examine the expression pattern of PTPN11, EPHA2 and those new critical nodes across almost 1500 CRC specimens and evaluate the prognostic values of these molecules. The project can not only investigate the clinical significance of the combine inhibition of PTPN11 and EPHA2 in CRC but also figure out the crosstalk of PTPN11 and EPHA2 signaling for the new CRC targets.