Stubbs Nolan M, Roady Tyler J, Schwermann Maximilian P, Eteshola Elias O, MacDonald William J, Purcell Connor, Ryspayeva Dinara, Verovkina Nataliia, Tajiknia Vida, Ghandali Maryam, Voong Viva, Lannigan Alexis J, Raufi Alexander G, Lawler Sean, Holder Sheldon L, Carneiro Benedito A, Cheng Liang, Safran Howard P, Graff Stephanie L, Dizon Don S, Mani Sendurai A, Seyhan Attila A, Sobol Robert W, Wong Eric T, Chen Clark C, Gokaslan Ziya, Taylor Martin S, Rivers Brian M, El-Deiry Wafik S
Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Legorreta Cancer Center, Brown University, Providence, RI 02903, USA.
Cancer Drug Resist. 2025 Jun 5;8:27. doi: 10.20517/cdr.2024.189. eCollection 2025.
Acquired resistance to molecularly targeted therapies remains a formidable challenge in the treatment of cancer, despite significant advancements over the last several decades. We critically evaluate the evolving landscape of resistance mechanisms to targeted cancer therapies, with a focus on the genetic, molecular, and environmental contributors across a variety of malignancies. Intrinsic mechanisms such as mutations, drug and drug target modifications, and, notably, the activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways are mechanisms different malignancies use to combat therapeutic effectiveness. Furthermore, extrinsic alterations to the tumor microenvironment contribute to therapeutic resistance. We highlight similarities and differences in mechanisms across a wide spectrum of cancers including hematologic malignancies, non-small cell lung cancer, gastrointestinal, breast, and prostate cancers, pancreatic, ovarian, endometrial, and intracranial gliomas. Emerging strategies to overcome resistance, including multi-targeted approaches, combination therapies, and exploitation of synthetic lethality, are all critically discussed. We advocate for a nuanced understanding of resistance mechanisms as a cornerstone for developing future therapeutic strategies, emphasizing the necessity for integrated approaches that encompass genomic insights and precision medicine to outpace the dynamic and complex nature of cancer evolution and therapy resistance.
尽管在过去几十年里取得了重大进展，但获得性分子靶向治疗耐药性仍然是癌症治疗中的一个巨大挑战。我们批判性地评估了靶向癌症治疗耐药机制的不断变化的格局，重点关注各种恶性肿瘤中的遗传、分子和环境因素。内在机制，如突变、药物和药物靶点修饰，尤其是丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3激酶（PI3K）/Akt信号通路的激活，是不同恶性肿瘤对抗治疗效果所采用的机制。此外，肿瘤微环境的外在改变也会导致治疗耐药性。我们强调了包括血液系统恶性肿瘤、非小细胞肺癌、胃肠道癌、乳腺癌和前列腺癌、胰腺癌、卵巢癌、子宫内膜癌和颅内神经胶质瘤在内的广泛癌症在机制上的异同。还对克服耐药性的新兴策略进行了批判性讨论，包括多靶点方法、联合治疗和利用合成致死性。我们主张对耐药机制有细致入微的理解，将其作为制定未来治疗策略的基石，强调采用综合方法的必要性，这些方法涵盖基因组学见解和精准医学，以超越癌症进化和治疗耐药性的动态复杂性。
