Labrie Marilyne, Li Allen, Creason Allison, Betts Courtney, Keck Jamie, Johnson Brett, Sivagnanam Shamilene, Boniface Christopher, Ma Hongli, Blucher Aurora, Chang Young Hwan, Chin Koei, Vuky Jacqueline, Guimaraes Alexander R, Downey Molly, Lim Jeong Youn, Gao Lina, Siex Kiara, Parmar Swapnil, Kolodzie Annette, Spellman Paul T, Goecks Jeremy, Coussens Lisa M, Corless Christopher L, Bergan Raymond, Gray Joe W, Mills Gordon B, Mitri Zahi I
Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, OR, USA.
NPJ Precis Oncol. 2021 Oct 19;5(1):92. doi: 10.1038/s41698-021-00232-w.
In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.
在一项试点研究中，我们评估了对三阴性乳腺癌患者的系列肿瘤样本进行实时深度分析的可行性，以确定在聚ADP-核糖聚合酶（PARP）抑制剂（PARPi）产生的治疗压力下出现的耐药机制和治疗机会。在一名BRCA突变的基底样乳腺癌长期幸存者中，显著的肿瘤破坏伴随着含有CD8效应细胞的免疫细胞的大量浸润，这与STING介导的免疫激活与PARPi和免疫治疗获益之间关联的临床前证据一致。该特殊反应者的肿瘤细胞在PARP抑制作用下经历了广泛的蛋白质网络重塑。相比之下，管腔雄激素受体快速进展者的生态系统变化极小，这可能是由于对PARP抑制作用不敏感。总之，基于肿瘤和免疫状态的变化，识别PARPi诱导的新出现变化可用于选择患者特异性联合治疗方案。
