Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies.
Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies.
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EGFR 突变的非小细胞肺癌对 TKI 的耐药性：从机制到新的治疗策略。
DOI：
10.3390/cancers14143337
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发表时间：
2022-07-08
期刊：
影响因子：
5.2
通讯作者：
Mountzios, Giannis
中科院分区：
文献类型：
--
作者：
Koulouris, Andreas;Tsagkaris, Christos;Corriero, Anna Chiara;Metro, Giulio;Mountzios, Giannis
晚期突变型非小细胞肺癌（NSCLC）对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）的耐药性构成了治疗挑战。耐药性可能是EGFR依赖性和独立性分子途径的结果。第一种通常包括T790 M，C797 S，L792 X和L718 X突变，而后者涉及HER 2和MET扩增，基因重排，PIK 3CA，MAPK信号传导和SCLC和上皮-间充质细胞转化的破坏。检测突变型无细胞DNA（cfDNA）的液体活检在突变型克隆变得临床明显之前检测突变型克隆方面具有主要潜力。新一代TKI、双特异性抗体和抗体-药物偶联物或TKI与其他TKI或化疗、免疫治疗和抗血管内皮生长因子（抗VEGF）的组合目前正在EGFR突变型NSCLC中使用或正在研究中。在EGFR突变型NSCLC脑转移中，血脑屏障（BBB）降低了TKI到达中枢神经系统（CNS）的能力，作为一种额外的耐药因素，目前可通过奥希替尼解决。化疗后再次激发EFGR TKI并与抗PD-1免疫治疗药物联合使用的可能性仍然矛盾。利用纳米载体改善EGFR TKI耐药NSCLC的药物递送在临床前环境中很有希望，但在临床背景下尚未确定。 晚期突变型非小细胞肺癌（NSCLC）对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）的耐药性构成了治疗挑战。本文综述了EGFR突变型NSCLC对TKI耐药机制的研究进展，并探讨其临床意义。EGFR依赖性和非依赖性分子途径有可能克服或规避EGFR靶向药物（包括第三代TKI、奥希替尼）的活性，对临床结局产生负面影响。由于第一代和第二代药物无法克服BBB和CNS中癌细胞的获得性耐药性，因此在接受EGFR-TKI治疗的患者中经常发生CNS转移。新一代TKI、靶向EGFR非依赖性耐药机制的TKI、双特异性抗体和抗体-药物偶联物或TKI与其他TKI或化疗、免疫治疗和抗血管内皮生长因子（抗VEGF）的组合目前正在EGFR突变型NSCLC中使用或正在研究中。检测突变无细胞DNA（cfDNA）的液体活检提供了在突变克隆变得临床明显之前攻击它们的机会之窗。总体而言，EGFR TKI耐药NSCLC构成了多方面的治疗挑战。绘制其潜在的突变景观，加速检测耐药机制和多样化的治疗策略对于疾病的管理至关重要。
Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant non-small cell lung cancer (NSCLC) constitutes a therapeutic challenge. Resistance may occur as a result of EGFR-dependent and independent molecular pathways. The first commonly includes T790M, C797S, L792X and L718X mutations, while the latter pertains to HER2 and MET amplifications, gene rearrangements, disruption in PIK3CA, MAPK signaling and SCLC and epithelial–mesenchymal cells transformation. Liquid biopsies detecting mutant cell-free DNA (cfDNA) have a major potential in the detection of mutant clones before they become clinically apparent. Newer-generation TKIs, bispecific antibodies and antibody-drug conjugates or combinations of TKIs with other TKIs or chemotherapy, immunotherapy and anti-vascular endothelial growth factors (anti-VEGFs) are currently in use or under investigation in EGFR mutant NSCLC. In EGFR mutant NSCLC metastatic to the brain, the blood–brain barrier (BBB) decreases the ability of TKIs to reach the central nervous system (CNS), acting as an additional resistance factor, which can presently be addressed with osimertinib. The potential of rechallenging EFGR TKIs after chemotherapy and combining it with anti-PD-1 immunotherapeutics remains ambivalent. Harnessing nanocarriers to improve drug delivery in EGFR TKIs-resistant NSCLC has been promising in preclinical settings, but it is yet to be determined in a clinical context. Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context of EGFR mutant NSCLC and discuss its clinical and therapeutic implications. EGFR-dependent and independent molecular pathways have the potential to overcome or circumvent the activity of EGFR-targeted agents including the third-generation TKI, osimertinib, negatively impacting clinical outcomes. CNS metastases occur frequently in patients on EGFR-TKIs, due to the inability of first and second-generation agents to overcome both the BBB and the acquired resistance of cancer cells in the CNS. Newer-generation TKIs, TKIs targeting EGFR-independent resistance mechanisms, bispecific antibodies and antibody-drug conjugates or combinations of TKIs with other TKIs or chemotherapy, immunotherapy and Anti-Vascular Endothelial Growth Factors (anti-VEGFs) are currently in use or under investigation in EGFR mutant NSCLC. Liquid biopsies detecting mutant cell-free DNA (cfDNA) provide a window of opportunity to attack mutant clones before they become clinically apparent. Overall, EGFR TKIs-resistant NSCLC constitutes a multifaceted therapeutic challenge. Mapping its underlying mutational landscape, accelerating the detection of resistance mechanisms and diversifying treatment strategies are essential for the management of the disease.
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影响因子：
30.8
作者：
Blakely CM;Watkins TBK;Wu W;Gini B;Chabon JJ;McCoach CE;McGranahan N;Wilson GA;Birkbak NJ;Olivas VR;Rotow J;Maynard A;Wang V;Gubens MA;Banks KC;Lanman RB;Caulin AF;St John J;Cordero AR;Giannikopoulos P;Simmons AD;Mack PC;Gandara DR;Husain H;Doebele RC;Riess JW;Diehn M;Swanton C;Bivona TG
通讯作者：
Bivona TG
影响因子：
16.6
作者：
Chabon JJ;Simmons AD;Lovejoy AF;Esfahani MS;Newman AM;Haringsma HJ;Kurtz DM;Stehr H;Scherer F;Karlovich CA;Harding TC;Durkin KA;Otterson GA;Purcell WT;Camidge DR;Goldman JW;Sequist LV;Piotrowska Z;Wakelee HA;Neal JW;Alizadeh AA;Diehn M
通讯作者：
Diehn M
影响因子：
11.2
作者：
Eberlein CA;Stetson D;Markovets AA;Al-Kadhimi KJ;Lai Z;Fisher PR;Meador CB;Spitzler P;Ichihara E;Ross SJ;Ahdesmaki MJ;Ahmed A;Ratcliffe LE;O'Brien EL;Barnes CH;Brown H;Smith PD;Dry JR;Beran G;Thress KS;Dougherty B;Pao W;Cross DA
通讯作者：
Cross DA
影响因子：
4.1
作者：
de Kock, Remco;van den Borne, Ben;Deiman, Birgit
通讯作者：
Deiman, Birgit
影响因子：
3.8
作者：
Arneth B
通讯作者：
Arneth B