PDF(Pubmed)
Abstract：
UNASSIGNED: Anaplastic lymphoma kinase (ALK)-targeted tyrosine kinase inhibitors (TKIs) improve patient survival; however, some patients develop ALK-TKI resistance with unidentified mechanisms. We investigated ErbB family and c-MET expression in patients with ALK-positive non-small cell lung cancer (NSCLC) to understand their roles in the ALK-TKI response.
UNASSIGNED: We studied 72 patients with advanced ALK-positive NSCLC with EML4-ALK fusion variant subtyping and immunostaining for c-MET, EGFR, HER2, and HER3 on tissue specimens both pre- (primary) and post-treatment (secondary) with ALK-TKI. We investigated the association of their expression with survival outcomes and assessed the effectiveness of combining ALK and EGFR inhibitors in ALK-positive NSCLC cell lines stimulated with the HER3-specific ligand HRG1.
UNASSIGNED: High expression of c-MET, EGFR, HER2, and HER3 was observed in 4.9%, 18.0%, 1.6%, and 25.8% of primary tumors, respectively, and 18.5%, 37.0%, 10.7%, and 35.7% of secondary tumors, respectively. HER3 overexpression in primary tumors showed inferior survival (P=0.132). In the subgroup with EML4-ALK variant 1/2 (V1/V2), HER3 overexpression was significantly associated with inferior survival in both primary and secondary tumors (P=0.022 and P=0.004, respectively). Combination treatment with lorlatinib and erlotinib significantly reduced HRG1-induced activation of RTK signaling in ALK-positive NSCLC cells.
UNASSIGNED: HER3 overexpression has potential as a prognostic marker in ALK-positive NSCLCs, including ALK-TKI naïve and treated cases, especially those with EML4-ALK V1/V2. Assessing HER3 expression may be crucial for treatment planning and outcome prediction in these patients.
UNASSIGNED: We studied 72 patients with advanced ALK-positive NSCLC with EML4-ALK fusion variant subtyping and immunostaining for c-MET, EGFR, HER2, and HER3 on tissue specimens both pre- (primary) and post-treatment (secondary) with ALK-TKI. We investigated the association of their expression with survival outcomes and assessed the effectiveness of combining ALK and EGFR inhibitors in ALK-positive NSCLC cell lines stimulated with the HER3-specific ligand HRG1.
UNASSIGNED: High expression of c-MET, EGFR, HER2, and HER3 was observed in 4.9%, 18.0%, 1.6%, and 25.8% of primary tumors, respectively, and 18.5%, 37.0%, 10.7%, and 35.7% of secondary tumors, respectively. HER3 overexpression in primary tumors showed inferior survival (P=0.132). In the subgroup with EML4-ALK variant 1/2 (V1/V2), HER3 overexpression was significantly associated with inferior survival in both primary and secondary tumors (P=0.022 and P=0.004, respectively). Combination treatment with lorlatinib and erlotinib significantly reduced HRG1-induced activation of RTK signaling in ALK-positive NSCLC cells.
UNASSIGNED: HER3 overexpression has potential as a prognostic marker in ALK-positive NSCLCs, including ALK-TKI naïve and treated cases, especially those with EML4-ALK V1/V2. Assessing HER3 expression may be crucial for treatment planning and outcome prediction in these patients.
摘要：
■间变性淋巴瘤激酶（ALK）靶向酪氨酸激酶抑制剂（TKIs）可改善患者生存率；然而，一些患者出现ALK-TKI耐药的机制不明.我们调查了ALK阳性非小细胞肺癌（NSCLC）患者的ErbB家族和c-MET表达，以了解它们在ALK-TKI反应中的作用。
■我们研究了72例晚期ALK阳性非小细胞肺癌患者的EML4-ALK融合变异亚型和c-MET免疫染色，EGFR,组织标本上的HER2和HER3在用ALK-TKI治疗前(初次)和后(二次)。我们研究了它们的表达与生存结果的关系，并评估了ALK和EGFR抑制剂在HER3特异性配体HRG1刺激的ALK阳性NSCLC细胞系中的有效性。
■c-MET的高表达，EGFR,HER2和HER3在4.9%中观察到，18.0%,1.6%,和25.8%的原发性肿瘤，分别,和18.5%，37.0%,10.7%,和35.7%的继发性肿瘤，分别。原发性肿瘤中的HER3过表达显示较差的生存率（P=0.132）。在具有EML4-ALK变体1/2（V1/V2）的亚组中，HER3过表达与原发性和继发性肿瘤的低生存率显著相关(分别为P=0.022和P=0.004)。氯拉替尼和厄洛替尼的联合治疗显著降低了ALK阳性NSCLC细胞中HRG1诱导的RTK信号激活。
■HER3过表达可能作为ALK阳性NSCLC的预后标志物，包括ALK-TKI幼稚和治疗病例，特别是那些与EML4-ALKV1/V2。评估HER3表达对于这些患者的治疗计划和结果预测可能至关重要。
■我们研究了72例晚期ALK阳性非小细胞肺癌患者的EML4-ALK融合变异亚型和c-MET免疫染色，EGFR,组织标本上的HER2和HER3在用ALK-TKI治疗前(初次)和后(二次)。我们研究了它们的表达与生存结果的关系，并评估了ALK和EGFR抑制剂在HER3特异性配体HRG1刺激的ALK阳性NSCLC细胞系中的有效性。
■c-MET的高表达，EGFR,HER2和HER3在4.9%中观察到，18.0%,1.6%,和25.8%的原发性肿瘤，分别,和18.5%，37.0%,10.7%,和35.7%的继发性肿瘤，分别。原发性肿瘤中的HER3过表达显示较差的生存率（P=0.132）。在具有EML4-ALK变体1/2（V1/V2）的亚组中，HER3过表达与原发性和继发性肿瘤的低生存率显著相关(分别为P=0.022和P=0.004)。氯拉替尼和厄洛替尼的联合治疗显著降低了ALK阳性NSCLC细胞中HRG1诱导的RTK信号激活。
■HER3过表达可能作为ALK阳性NSCLC的预后标志物，包括ALK-TKI幼稚和治疗病例，特别是那些与EML4-ALKV1/V2。评估HER3表达对于这些患者的治疗计划和结果预测可能至关重要。
