In the era of precision medicine, implementing molecularly targeted therapies against specific vulnerabilities of tumour cells is revolutionizing cancer management. One representative is poly (ADP-ribose) polymerase (PARP) inhibitors that eliminate tumour cells deficient in homologous recombination, a pathway essential for DNA double-strand break repair. Unfortunately, pre-existing and acquired PARP inhibitors resistance emerge as a clinical hurdle. The cellular mechanisms underpinning PARP inhibitors resistance have been summarized to four main categories including disrupted cellular availability, decreased PARP trapping, reactivation of homologous recombination, and restoration of replication fork stability.1 However, investigations on deciphering the resistance and potentiating PARP inhibitors are primarily focused on tumour cells, and the practicability of targeting noncancerous components within the tumour microenvironment (TME) is underestimated.
Cancer-associated fibroblasts (CAFs) are active players in the TME with versatile functions such as matrix remodeling and the crosstalk with tumour cells and infiltrating immune cells. DNA damage due to chemotherapy or radiotherapy kills cancer cells and simultaneously contributes to CAFs activation, and reprogrammed CAFs undergo significant phenotype transitions, thereby stimulating tumour growth, promoting cancer invasion, and mediating the resistance to therapies, indicating the potential of CAFs as targets for optimizing therapeutic strategies against cancer.2 In addition to similar lethal mechanism between platinum and PARP inhibitors, resistance to platinum-based chemotherapies is a strong predictor for PARP inhibitors resistance. Therefore, we hypothesized that PARP inhibitors could activate CAFs within the TME and targeting CAFs might augment their antitumor capabilities.
Our research published in the npj Precision Oncology revealed that PARP inhibitors promoted CAFs activation by enhancing the autocrine of C-C chemokine ligand 5 (CCL5) mediated by NF-κB pathway and CCL5 blockade significantly blunted the reprogramming of CAFs conditioned by PARP inhibitors and boosted the antitumour effects of PARP inhibitors in vitro and in vivo.3 The results were consolidated in both xenograft models injected with BRCA-deficient or BRCA-proficient ovarian cancer cells and BRCA-deficient breast cancer cells, signifying that the efficacy gain was irrespective of BRCA status of cancer in mouse models. Besides hinting at the relevance between noncancerous cells in TME and resistance to targeted anticancer therapies, our study indicates that targeting them such as CAFs could potentially help to overcome drug resistance, a prevailing challenge for cancer management. To corroborate PARP inhibitors-induced CAFs activation and resultant influences on resistance, we should examine the responses of germline BRCA-mutated CAFs to PARP inhibitors and decipher how upregulated CCL5 autocrine contributes to CAFs activation and mediates PARP inhibitors resistance.
As a double-edged sword in cancer, CCL5/CCR5 axis abets tumour progression and bolsters antitumor immunity by recruiting immune cells to the TME, therefore intensifying the immunotherapy response in multiple cancers.4 Though the outcomes of immune checkpoint blockade (ICB) monotherapy in epithelial ovarian cancer is relatively disappointing, the therapeutically synergistic treatment using PARP inhibitors and ICB holds promise because PARP inhibitors triggers adaptive upregulation of programmed death ligand l expression.5 Whether the enhanced antitumor effects of PARP inhibitors due to CCL5 blockade are attributable to immune microenvironment modulation warrants further investigations. Ongoing clinical trials are evaluating anti-CCR5 monoclonal antibody Leronlimab for antitumor therapies (NCT04504942) and the only approved drug targeting CCL5/CCR5 axis Maraviroc for combination with ICB to treat metastatic colorectal cancer (NCT03274804). However, clinical trials that target CAFs-derived CCL5 to potentiate PARP inhibitors has not been launched yet.
1 Noordermeer, S. M. & van Attikum, H. PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells. Trends Cell Biol 29, 820-834 (2019).
2 Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer 20, 174-186 (2020).
3 Li, X. et al. PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer. NPJ Precis Oncol 5, 49 (2021).
4 Aldinucci, D., Borghese, C. & Casagrande, N. The CCL5/CCR5 Axis in Cancer Progression. Cancers 12, 1765 (2020).
5 Stewart, R. A., Pilié, P. G. & Yap, T. A. Development of PARP and Immune-Checkpoint Inhibitor Combinations. Cancer Research 78, 6717-6725 (2018).