靶向治疗以高效、低毒的特点成为最有希望的癌症治疗方案之一，然而普遍发生的肿瘤耐药极大的制约了其临床应用。因此，对其分子机理的研究成为当前非常急迫的热点问题。前期研究发现，抑制剂阻断黑色素瘤细胞中MAPK通路导致RTK在耐药性进展过程中被激活，并重新编排、整合细胞中的信号网络，绕开已被阻断的原有关键通路，利用其它旁支通路维系细胞的生长、代谢，为进一步演化出稳定耐药机制（可遗传）提供有力的庇护。申请者计划通过鉴定在肿瘤靶向药物耐药进程中，参与保护肿瘤细胞的RTK，并研究其具体的分子调控机理。研究思路是，利用高通量测序技术，对肿瘤耐药过程的转录组学进行了分析，结合临床样本的高通量测序数据，选定了cKit和ROS1极有可能是参与调控肿瘤靶向药物耐受的RTK；在体内、外模型中通过失去功能实验和获得功能实验两个角度，验证cKit和ROS1对肿瘤耐药早期进程的功能，并通过对其下游通路的分析，揭示其分子机

V600E/KBRAF mutants lead to constitutive activation of the RAS-RAF-MEK-MAPK pathway in a RAF dimerization independent manner, promoting uncontrolled tumor cell proliferation. Targeting these specific mutants by small molecules reproducibly elicited tumor shrinkage response and quickly relieved symptoms in clinic. However, tumor relapse, known as “drug resistance”, is almost universal, which presents a formidable obstacle to long-term therapeutic benefits. Understanding and overcoming innate and acquired drug resistance became a critical and urgent challenge in this field. Generally, those mechanisms fell into two distinct categories, 1) MAPK reactivation including secondary N-RAS mutations, COT/MAP3K8 kinase overexpression, MEK mutation, BRAF amplification and alternative splicing, NF1 down regulation, and 2) activation of a MAPK-redundant survival pathway including upregulation of receptor tyrosine kinases (RTK) such as platelet-derived growth factor receptor β (PDGFRβ) or insulin-like growth factor 1 receptor (IGF1R), PI3K/AKT mutation, cAMP/PKA upregulation, etc.