Overcoming Central β-Sheet #6 (Cβ6) ALK Mutation (L1256F), TP53 Mutations and Short Forms of EML4-ALK v3/b and v5a/b Splice Variants are the Unmet Need That a Re-Imagined 5th-Generation (5G) ALK TKI Must Deliver.

IF 5.1 Q1 ONCOLOGY
Lung Cancer: Targets and Therapy Pub Date : 2024-02-27 eCollection Date: 2024-01-01 DOI:10.2147/LCTT.S446878
Alexandria T M Lee, Sai-Hong Ignatius Ou
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引用次数: 0

Abstract

Despite the development and approval of seven anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) spanning over three "generations" since the discovery of ALK fusion positive (ALK+) non-small cell lung cancer (NSCLC), there remains intrinsic and acquired resistances to these approved TKIs. Currently, a fourth-generation (4G) ALK TKI, NVL-655, is being developed to attack some of the unmet needs such as compound resistance mutations in cis. However, EML4-ALK variant 3 and TP53 mutations are intrinsic genomic alterations that negatively modulate efficacy of ALK TKIs. Potentially, in the shifting landscape where lorlatinib should be the first-line ALK TKI of choice based on the CROWN trial, the central β-sheet #6 (Cβ6) mutation ALK L1256F will be the potential acquired resistance mutation to lorlatinib which may be resistant to current ALK TKIs. Here we opine on what additional capacities a putative fifth-generation (5G) ALK TKI will need to possess if it can be achieved in one single molecule. We propose randomized trial schemas targeting some of the intrinsic resistance mechanisms that will lead to approval of a prototypic fifth-generation (5G) ALK TKI and actually be beneficial to ALK+ NSCLC patients rather than just design a positive pivotal superiority trial for the sole purpose of drug approval.

克服中枢β片6 (Cβ6) ALK突变(L1256F)、TP53突变和EML4-ALK v3/b和v5a/b的短式剪接变异是重新构想的第五代(5G) ALK TKI必须满足的需求。
尽管自发现 ALK 融合阳性(ALK+)非小细胞肺癌(NSCLC)以来,已经开发并批准了七种无性淋巴瘤激酶(ALK)酪氨酸激酶抑制剂(TKIs),时间跨度超过三 "代",但这些已批准的 TKIs 仍然存在固有和获得性抗药性。目前,第四代(4G)ALK TKI--NVL-655 正在开发中,以满足一些尚未满足的需求,如顺式复合耐药突变。然而,EML4-ALK 变异 3 和 TP53 突变是固有的基因组改变,会对 ALK TKIs 的疗效产生负面影响。根据 CROWN 试验,洛拉替尼应成为一线 ALK TKI 的首选,在这种不断变化的情况下,中心 β-片6(Cβ6)突变 ALK L1256F 有可能成为洛拉替尼的获得性耐药突变,它可能对目前的 ALK TKIs 产生耐药性。在此,我们认为,如果能在单一分子中实现,推定的第五代(5G)ALK TKI 还需要具备哪些能力。我们提出了针对一些内在耐药机制的随机试验方案,这些机制将促使原型第五代 (5G) ALK TKI 获得批准,并使 ALK+ NSCLC 患者真正受益,而不是仅仅为了获得药物批准而设计一个积极的关键性优越性试验。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.10
自引率
0.00%
发文量
10
审稿时长
16 weeks
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