Department of Biochemistry; Massey Cancer Center; Virginia Commonwealth University; Richmond, VA USA.
Cancer Biol Ther. 2014 Jun 1;15(6):653-4. doi: 10.4161/cbt.28504. Epub 2014 Mar 11.
Receptor tyrosine kinases play important roles in the biology of many tumor cell types. In approximately 10% of non-small cell lung cancer (NSCLC) patients mutational activation of the epidermal growth factor receptor (EGFR) results in tumor cells that are exquisitely addicted to signaling by this receptor. (1) Thus expression of mutant active EGFR but in general not wild-type EGFR predisposes NSCLC cells to inhibitors of EGFR/ErbB2. Use of EGFR inhibitory agents such as gefitinib for this subset of NSCLC patients causes tumor regression and disease stabilization for 12-18 mo, after which tumor cells become resistant to the drug. (2) Initial studies identified a second mutation within the EGFR, which results in the resistance of the tyrosine kinase to gefitinib, as a major cause of reduced tumor control. (3) This has resulted in the development of newer EGFR inhibitors, e.g., afatinib, which inhibited double mutant EGFR. (4) In a subset of these patients, however, resistance to gefitinib was not associated with EGFR mutations. (5) Clearly, other mechanisms of gefitinib resistance must be at play.
受体酪氨酸激酶在许多肿瘤细胞类型的生物学中发挥着重要作用。在大约 10%的非小细胞肺癌（NSCLC）患者中，表皮生长因子受体（EGFR）的突变激活导致肿瘤细胞对该受体的信号传导产生高度依赖。（1）因此，表达突变的活性 EGFR，但通常不是野生型 EGFR，使 NSCLC 细胞容易受到 EGFR/ErbB2 的抑制剂的影响。对于这部分 NSCLC 患者，使用 EGFR 抑制剂如吉非替尼会导致肿瘤消退和疾病稳定 12-18 个月，之后肿瘤细胞对药物产生耐药性。（2）最初的研究确定了 EGFR 内的第二个突变，这导致酪氨酸激酶对吉非替尼的耐药性，是肿瘤控制降低的主要原因。（3）这导致了新型 EGFR 抑制剂的开发，例如 afatinib，它可以抑制双突变 EGFR。（4）然而，在这些患者的亚组中，吉非替尼的耐药性与 EGFR 突变无关。（5）显然，吉非替尼耐药性的其他机制一定在起作用。
