The Mechanism Of The TP53 Conformational Mutations Promoting Tumor Vasculogenic Mimicry And Its Possible Impact On TKI Therapy Of EGFR Mutated NSCLC

Objective:To investigate the effect and molecular mechanism of conformational mutant p53 in promoting vasculogenic mimicry(VM)in non-small cell lung cancer(NSCLC)and to explore whether the p53 conformational mutation can be used as a possible biomarker for EGFR-TKI combined with VEGFR2 inhibitors to delay or overcome TKI resistance.Method:HCC827 cells were transfected with different types of mutant p53,the angiogenesis ability was detected by tube formation assay and ELISA assay;HCC827 cells were transfected with different types of mutant p53,the sensitivity of NSCLC cells with TP53 conformational mutation/EGFR mutation to combination of VEGFR2 inhibitor with TKI treatment was detected by MTT assay;H1299 cells were transfected with different types of mutant p5 3,the molecular mechanism of tumor VM promotion was analyzed by co-IP assay,agarose gel assay,ChIP-qPCR assay and luciferase reporter gene assay.Result:Whole-exome sequencing analysis of 6 NSCLC patients with EGFR mutation showed that the conformational mutant p53 may benefited from EGFR-TKI and cabozantinib combination therapy.Functional analysis showed that the conformational mutants p53C238F、p53C238Y、p53R175H could promote more tumor VM compared with contact mutants p53R273H.The mechanism analysis showed that conformational mutants p53 could be more likely to aggregate with p63 and p73,release the negative regulation of VEGFR2 transcription by p63 and p73,and promote the expression of VEGFR2.Conclusion:The conformational mutant p53C238F、p53C238Y、p53R175H can promote tumor VM via releasing the negative regulation of VEGFR2 transcription by p63 and p73,thereby contributing conformational mutant p53/EGFR mutant patients to TKI resistance.EGFR-TKI combined with cabozantinib(or other VEGFR2 inhibitors)may be a novel strategy for the clinical treatment of NSCLC patient with EGFR mutation and conformational mutant p53.