Tsamis Ioannis, Gomatou Georgia, Chachali Stavroula Porfyria, Trontzas Ioannis Panagiotis, Patriarcheas Vasileios, Panagiotou Emmanouil, Kotteas Elias
Oncology Unit, Third Department of Internal Medicine, "Sotiria" General Hospital for Diseases of the Chest, National and Kapodistrian University of Athens, Messogion Ave 152, 11527, Athens, Greece.
4th Department of Internal Medicine, "Atticon" General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Clin Transl Oncol. 2023 Jan;25(1):10-20. doi: 10.1007/s12094-022-02849-0. Epub 2022 Jun 21.
Targeted therapy for oncogenic genetic alterations has changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). Mutations in the BRAF gene are detected in approximately 4% of patients and result in hyper-activation of the MAPK pathway, leading to uncontrolled cellular proliferation. Inhibition of BRAF and its downstream effector MEK constitutes a therapeutic strategy for a subset of patients with NSCLC and is associated with clinical benefit. Unfortunately, the majority of patients will develop disease progression within 1 year. Preclinical and clinical evidence suggests that resistance mechanisms involve the restoration of MAPK signaling which becomes inhibition-independent due to upstream or downstream alterations, and the activation of bypass pathways, such as the PI3/AKT/mTOR pathway. Future research should be directed to deciphering the mechanisms of cancer cells' oncogenic dependence, understanding the tissue-specific mechanisms of BRAF-mutant tumors, and optimizing treatment strategies after progression on BRAF and MEK inhibition.
针对致癌基因改变的靶向治疗已经改变了晚期非小细胞肺癌（NSCLC）的治疗模式。BRAF基因的突变在约4%的患者中被检测到，其导致MAPK通路的过度激活，从而导致细胞增殖失控。抑制BRAF及其下游效应物MEK构成了一部分NSCLC患者的治疗策略，并且与临床获益相关。不幸的是，大多数患者会在1年内出现疾病进展。临床前和临床证据表明，耐药机制包括MAPK信号通路的恢复，该通路由于上游或下游改变而变得不依赖于抑制，以及旁路途径的激活，如PI3/AKT/mTOR途径。未来的研究应致力于破解癌细胞致癌依赖性的机制，理解BRAF突变肿瘤的组织特异性机制，以及优化BRAF和MEK抑制治疗进展后的治疗策略。
