Abstract:
Neurotrophic receptor kinase (NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors, and tropomyosin receptor kinase (TRK) has been considered as an attractive therapeutic target for \"pan-cancer\" harboring these fusions. Currently, two generations TRK inhibitors have been developed. The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. However, xDFG (TRKAG667C/A/S, homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field.
摘要:
神经营养受体激酶(NTRK)融合是多种儿童和成人实体瘤的可行致癌驱动因素,原肌球蛋白受体激酶(TRK)被认为是具有这些融合的“泛癌症”的有吸引力的治疗靶标。目前,已经开发了两代TRK抑制剂。具有代表性的第二代抑制剂selitrectinib和repotrectinib旨在克服由溶剂前沿和看门人靶突变引起的第一代抑制剂larotrectinib或entrectinib的临床获得性耐药性。然而,xDFG(TRKAG667C/A/S,同源TRKCG696C/A/S)和一些双重突变仍然赋予对selitrectinib和repotrectinib的抗性,克服这些耐药性代表了一个主要的未满足的临床需求。在这次审查中,我们总结了第一代和第二代TRK抑制剂的获得性耐药机制,并首次提出了新兴的选择性II型TRK抑制剂来克服xDFG突变介导的耐药性。此外,我们总结了我们对这一领域新挑战和未来方向的看法。