Dempke Wolfram C M, Fenchel Klaus
University of Munich, Medical Clinic III, Campus Grosshadern, Munich, Germany.
Medical Oncology Centre, Saalfeld, Germany.
Transl Cancer Res. 2024 Nov 30;13(11):6540-6549. doi: 10.21037/tcr-24-690. Epub 2024 Nov 27.
Non-small cell lung cancer (NSCLC) represents over 80% of lung cancer cases and has a high mortality worldwide, however, targeting common epidermal growth-factor receptor (EGFR) alterations (i.e., del19, L858R) has provided a paradigm shift in the treatment of NSCLC. Uncommon EGFR mutations, however, show variable efficacy to EGFR-targeted drugs depending on the molecular alterations within exons 18-21 which underlying biological mechanism are far from being clear. The substitution mutations of G719X in exon 18, L861Q in exon 21, S768I in exon 20, and exon 20 insertions are the most frequent mutations among the uncommon mutations. The development of fourth-generation EGFR-tyrosine kinase inhibitor (TKIs) has gained increased interest as these drugs are able to inhibit resistance mutations (e.g., C797S) often detected in NSCLC patients' resistance to third-generation EGFR TKIs. BDTX-1535 is an orally bioavailable, brain-penetrating, mutation-selective, irreversible EGFR inhibitor with significant antitumour activity in NSCLCs and glioblastomas (phase I/II trials ongoing). It is a fourth-generation EGFR inhibitor that was found to overcome resistance to osimertinib in preclinical models and has shown promising activity in NSCLC patients harbouring C797S mutations. In experimental models BDTX-1535 was found to inhibit all common EGFR mutations and more than 50 of uncommon mutations including T790M, C797S, L718X, E709X, S784F, V834L and A289V, however, exon 20 insertions are inhibited to a much lesser extent. In addition, mutations in the extracellular domain of the EGF receptor (e.g., EGFRvII, III, IV) can be blocked as well. It should be noted that in up to 50% of all NSCLC patients who progress following osimertinib or other EGFR TKI therapy no underlying resistance mechanism can be identified suggesting that non-mutational signal transduction pathways may also be operative, and intratumoural heterogeneity has been found to be a major contributor to resistance and it consists of three main mechanisms: (I) drug-tolerant persister (DTP) cells, (II) chromosomal instability, and (III) extrachromosomal extracellular DNA (ecDNA) (seen in over 50% of NSCLCs) suggesting that novel EGFR TKIs will include many challenges in sufficiently targeting on-target resistance mechanisms. The development of novel drugs that can overcome TKI resistance in NSCLC patients harbouring the C797S mutation and beyond is, therefore, eagerly warranted.
非小细胞肺癌（NSCLC）占肺癌病例的80%以上，在全球范围内死亡率很高。然而，针对常见的表皮生长因子受体（EGFR）改变（即del19、L858R）已为NSCLC的治疗带来了范式转变。然而，罕见的EGFR突变对EGFR靶向药物的疗效因外显子18 - 21内的分子改变而异，其潜在生物学机制尚不清楚。外显子18中的G719X、外显子21中的L861Q、外显子20中的S768I以及外显子20插入是罕见突变中最常见的突变。第四代EGFR酪氨酸激酶抑制剂（TKIs）的研发引起了越来越多的关注，因为这些药物能够抑制NSCLC患者对第三代EGFR TKIs耐药时经常检测到的耐药突变（如C797S）。BDTX - 1535是一种口服生物可利用、可穿透血脑屏障、具有突变选择性的不可逆EGFR抑制剂，在NSCLC和胶质母细胞瘤中具有显著的抗肿瘤活性（正在进行I/II期试验）。它是一种第四代EGFR抑制剂，在临床前模型中被发现可克服对奥希替尼的耐药性，并且在携带C797S突变的NSCLC患者中显示出有前景的活性。在实验模型中，BDTX - 1535被发现可抑制所有常见的EGFR突变以及50多种罕见突变，包括T790M、C797S、L718X、E709X、S784F、V834L和A289V，然而，外显子20插入的抑制程度要小得多。此外，表皮生长因子受体细胞外结构域的突变（如EGFRvII、III、IV）也可被阻断。需要注意的是，在接受奥希替尼或其他EGFR TKI治疗后病情进展的所有NSCLC患者中，高达50%的患者无法确定潜在的耐药机制，这表明非突变信号转导途径也可能起作用，并且肿瘤内异质性已被发现是耐药的主要原因，它由三种主要机制组成：（I）药物耐受持久性（DTP）细胞，（II）染色体不稳定性，以及（III）染色体外细胞外DNA（ecDNA）（在超过50%的NSCLC中可见），这表明新型EGFR TKIs在充分靶向靶点耐药机制方面将面临许多挑战。因此，迫切需要开发能够克服携带C797S突变及其他情况的NSCLC患者中TKI耐药的新型药物。
