Tabbò Fabrizio, Reale Maria Lucia, Bironzo Paolo, Scagliotti Giorgio V
Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, TO, Italy.
Transl Lung Cancer Res. 2020 Dec;9(6):2545-2556. doi: 10.21037/tlcr-20-372.
Anaplastic lymphoma kinase () translocations are responsible of neoplastic transformation in a limited subset of non-small cell lung cancer (NSCLC) patients. In recent years outcomes of these patients improved due to the development and clinical availability of specific and extremely active targeted therapies [i.e., next-generation Tyrosine Kinase Inhibitors (TKI)]: ALK+ patients are now reaching impressive results when treated with more potent inhibitors upfront with an average median progression-free survival (mPFS) around 35 months. However, under drug pressure, cancer cells develop resistance and patients eventually progress. Multiple mechanisms of intrinsic or acquired resistance have been extensively characterized. Less potent ALK inhibitors (ALKi)-like crizotinib-usually tend to induce a large spectrum of secondary intra-kinase mutations; however, these alterations may be observed also after sequential administration of multiple ALKi. Noteworthy, neoplastic cells may evade ALK targeting through a myriad of different mechanisms involving cell-stroma interaction, activation of parallel signaling pathways, intracellular downstream adaptation and histological reshaping, as relevant molecular events. Often these phenomena are restricted to a limited number of cases or even can be patient-specific, thus hindering the development of therapeutic strategies largely applicable. Consequently, the recognition of specific resistance mechanisms seldom translates in clinical opportunities. Management of ALK+ patients is drastically changed and deciphering the molecular biology underlying this disease during treatment is of paramount relevance. The bedrock of resistance to TKI is that, after the diagnosis, we face with a different disease that needs to be re-characterized through tissue or/and liquid biopsies. Understanding molecular pathways driving the resistant phenotype will give us the chance to know what we are dealing with and, rather than choose an empirical approach, will help us to properly define the best targeted treatment for these patients.
间变性淋巴瘤激酶（ALK）易位在非小细胞肺癌（NSCLC）患者的有限亚组中导致肿瘤转化。近年来，由于特异性且活性极高的靶向治疗药物[即新一代酪氨酸激酶抑制剂（TKI）]的研发及临床应用，这些患者的预后得到改善：ALK阳性患者在初始接受更强效抑制剂治疗时，目前已取得令人瞩目的结果，平均无进展生存期（mPFS）约为35个月。然而，在药物压力下，癌细胞会产生耐药性，患者最终会病情进展。内在或获得性耐药的多种机制已得到广泛研究。效力较弱的ALK抑制剂（ALKi），如克唑替尼，通常倾向于诱导大量继发性激酶内突变；然而，在序贯使用多种ALKi后也可能观察到这些改变。值得注意的是，肿瘤细胞可能通过多种不同机制逃避ALK靶向，这些机制涉及细胞-基质相互作用、平行信号通路的激活、细胞内下游适应和组织学重塑等相关分子事件。这些现象通常局限于少数病例，甚至可能具有患者特异性，从而阻碍了广泛适用的治疗策略的开发。因此，对特定耐药机制的识别很少能转化为临床机会。ALK阳性患者的治疗管理已发生巨大变化，在治疗过程中解读该疾病背后的分子生物学至关重要。对TKI耐药的根本原因是，在诊断后，我们面对的是一种需要通过组织活检或/和液体活检重新进行特征描述的不同疾病。了解驱动耐药表型的分子途径将使我们有机会了解我们所面对的情况，而不是采用经验性方法，这将有助于我们为这些患者正确确定最佳靶向治疗方案。
