Coleman Niamh, Subbiah Vivek, Pant Shubham, Patel Keyur, Roy-Chowdhuri Sinchita, Yedururi Sireesha, Johnson Amber, Yap Timothy A, Rodon Jordi, Shaw Kenna, Meric-Bernstam Funda
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA.
NPJ Precis Oncol. 2021 Dec 1;5(1):99. doi: 10.1038/s41698-021-00240-w.
Acquired resistance to molecular targeted therapy is a significant challenge of the precision medicine era. The ability to understand these mechanisms of resistance may improve patient selection and allow for the development of rationally designed next-line or combination treatment strategies and improved patient outcomes. AKT is a critical effector of the phosphoinositide 3-kinase signaling cascade, one of the most commonly activated pathways in human cancer. Deregulation of signaling pathways, such as RAF/MEK/ERK are previously described mechanisms of resistance to AKT/PI3K inhibitors. Mutations in the mTOR gene, however, are exceedingly rare. We present a case of acquired mTOR resistance, following targeted AKT inhibition, and subsequent response to mTOR1/2 inhibitor in a patient with metastatic endometrial cancer, the first documented response to ATP-competitive mTOR inhibition in this setting. This case supports mTOR mutation as a mechanism of resistance, and underscores the importance of tumor molecular profiling, exemplifying precision medicine in action.
获得性分子靶向治疗耐药是精准医学时代的一项重大挑战。了解这些耐药机制的能力可能会改善患者的选择，并有助于制定合理设计的二线或联合治疗策略，从而改善患者的治疗效果。AKT是磷酸肌醇3激酶信号级联反应的关键效应器，该信号级联反应是人类癌症中最常被激活的信号通路之一。信号通路失调，如RAF/MEK/ERK，是先前描述的对AKT/PI3K抑制剂耐药的机制。然而，mTOR基因的突变极为罕见。我们报告了一例转移性子宫内膜癌患者在接受靶向AKT抑制后获得性mTOR耐药，随后对mTOR1/2抑制剂产生反应的病例，这是该情况下首次记录到的对ATP竞争性mTOR抑制的反应。该病例支持mTOR突变作为一种耐药机制，并强调了肿瘤分子谱分析的重要性，体现了精准医学的实际应用。
