Division of Molecular Carcinogenesis and Oncode Institute. The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
Nat Commun. 2020 Jun 22;11(1):3157. doi: 10.1038/s41467-020-16952-9.
Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibitor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibitor therapy.
耐药性靶向癌症药物被认为是由于高药物剂量施加的选择性压力引起的。同一致癌信号通路中的多个成分的部分抑制可能会加起来完全抑制通路，同时减少每个成分获得耐药性突变的选择性压力。我们在这里报告了在 EGFR 突变 NSCLC 中测试这种多低剂量 (MLD) 治疗模型的结果。我们表明，当在 3D（RAF+MEK+ERK）或 4D（EGFR+RAF+MEK+ERK）抑制剂组合中使用时，只需 20%的个体有效药物剂量就足以完全阻断 MAPK 信号传导和增殖。重要的是，用 MLD 治疗的 EGFR 突变 NSCLC 细胞不会产生耐药性。使用几种动物模型，我们发现 MLD 治疗可持久缓解，而没有相关毒性。我们的数据支持这样一种观点，即 MLD 治疗即使对那些已经对第三代 EGFR 抑制剂治疗产生耐药性的患者也可能带来临床获益。
