We have previously identified a molecular subtype in solid tumors which is characterised by STING mediated immune signalling due to abnormal DNA as a result of loss of DNA repair mechanisms. This subtype is characterised by activation of cytokines, such as CXCL10, which attract lymphocytic infiltration and upregulate immune checkpointing genes like PD-L1. This subtype is identified by a 44 gene expression signature, the DNA damage response deficient (DDRD) assay. It is well recognised, that while loss of DNA repair can sensitize to DNA damaging chemotherapy, it may also confer resistance to anti-microtubule agents. We hypothesized the DDRD positive molecular subtype in prostate cancer would confer a worse outcome following docetaxel treatment.
We used siRNA-mediated knockdown of DNA repair genes in DU145 cells to test for activation of the DDRD immune signal and sensitivity to docetaxel versus DNA damaging agents. We obtained FFPE diagnostic core biopsies from 52 men with Castrate Resistant Prostate Cancer (CRPC) treated with Docetaxel. Response to docetaxel was measured as a >50% decline in Prostate Specific Antigen (PSA). Samples were microarray profiled, signature scored and defined as DDRD positive or negative.
siRNA mediated knockdown of BRCA1, BRCA2 and ATM resulted in increased resistance to docetaxel and increased sensitivity to cisplatin. Ten patients (19.23%) were DDRD positive and 42 (80.76%) were DDRD negative; 80% of DDRD positive and 47% of DDRD negative patients failed to benefit from docetaxel. DDRD positive tumour samples demonstrated an association with poorer overall survival post-docetaxel (HR 0.464; 95% CI 0.13 to 0.89; p = 0.0317; Median survival DDRD positive 12.43months vs. DDRD negative 21.83 months).
The DDRD positive molecular subtype of prostate cancer, characterised by an immune response to DNA damage, has a reduced benefit from docetaxel. We intend to validate this observation in the STAMPEDE trial, investigating advanced prostate cancer patients who received docetaxel as primary therapy. These studies may lead to clinical trials where DDRD positive patients receive specific DNA damaging agents like carboplatin or an immune targeted therapy such as a PD-L1 inhibitor.
Clinical trial identification
Legal entity responsible for the study
Queens University Belfast
Cancer Research UK
S. Walker: This Author is an employee for ALMAC diagnostics.
N. McCabe: Is an employee of Almac Daignostics and her research is funded by Almac in part.
L. Hill: Is an employee of ALMAC diagnostics and her work is funded by ALMAC.
R. Kennedy: Employee of Almac diagnostics.
All other authors have declared no conflicts of interest.