Ziyu Li

Sensitivity of Platinum‐Based Chemotherapy and Efficacy of Arsenic Trioxide‐Based Non‐Platinum Chemotherapy Following the Progression of PARPi Maintenance Therapy: A Real‐World Study

ABSTRACT Background Cross‐resistance is observed between platinum and Poly (ADP‐ribose) polymerase inhibitors (PARPi). We aim to propose the definition of PARPi resistance and demonstrate the best therapeutic strategy for patients with PARPi resistance. Methods A retrospective analysis was performed on patients diagnosed with epithelial ovarian cancer from October 2015 to November 2022. Patients were treated with PARPi for more than 6 months and received chemotherapy after progression. Results Totally, 41 patients were enrolled, with 21 receiving PARPi for 6 to 12 months and 20 for more than 12 months. The median duration of PARPi was 12 months, and the median time to second progression (TTSP) was 3.45 months (range, 1.0–20.2 months). The Kaplan–Meier and Cox analysis revealed a significantly shorter TTSP for patients who received PARPi for more than 12 months compared to those for 6 to 12 months. After PARPi resistance, 34 (82.9%) received platinum‐based chemotherapy, with an overall response rate (ORR) of 26.5% (9/34). Seven patients (17.1%) received arsenic trioxide (ATO)‐based chemotherapy, with an ORR of 57.1% (4/7). During subsequent chemotherapy, 12/34 patients switched to ATO‐based chemotherapy due to progression, of which five cases were evaluated as effective (41.7%). Conclusion PARPi resistance has a negative impact on the subsequent chemotherapy. The progression of the disease beyond 6 to 12 months should be considered as acquired resistance. Non‐platinum chemotherapy, such as ATO‐based combined sequential chemotherapy, may emerge as the preferred option for patients with PARPi resistance.

The estrogen response in fibroblasts promotes ovarian metastases of gastric cancer

Younger premenopausal women are more prone to developing ovarian metastases (OM) of gastric cancer (GC) than metastases of other organs; however, the molecular mechanisms remain unclear. Here we perform single-cell RNA sequencing on 45 tumor samples from 18 GC patients with OM. Interestingly, fibroblasts in OM of GC express high levels of estrogen receptor (ER) and midkine (MDK), interacting with tumor cells through activating ER-MDK-LRP1 (low-density lipoprotein receptor-related protein 1) signaling axis. Functional experiments demonstrate that estrogen stimulation induces MDK secretion by ovarian fibroblasts, and binding of MDK to LRP1 increases GC cell migration and invasion. Furthermore, in vivo, estrogen stimulation remarkably augments ovarian engraftment and metastasis of LRP1