We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors.
Evidence also increasingly supports that platinum drugs and inhibitors of poly (ADP-ribose) polymerase, or PARP, are particularly effective in the treatment of germline BRCA-mutant cancers, including TNBC.
Recently, we have seen 3 newly approved targeted therapies for TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation associated breast cancer (gBRCAm-BC) and most recently the checkpoint inhibitor, atezolizumab in combination with nab-paclitaxel for programmed death-ligand 1 (PD-L1+) advanced TNBC.
Expression of mutant p53 (mtp53) R273H associates with increased cell elasticity, survival under serum deprivation conditions, and increased Poly (ADP ribose) polymerase 1 (PARP1) on the chromatin in the AA-derived TNBC breast cancer cell line MDA-MB-468.
Recent evidence suggests that some patients with TNBC harbour germ-line mutations in DNA repair genes which may render their tumours susceptible to novel therapies such as treatment with PARP inhibitors.
Collectively, these findings strongly suggest that combining mTOR inhibitors and PARP inhibitors would be an effective therapeutic approach to treat BRCA-proficient TNBC patients.
The combination of the PARP inhibitor olaparib and rapamycin synergistically inhibited cell proliferation in non-small cell lung cancer (NSCLC) cells, and even in triple negative breast cancer (TNBC) cells with BRCA1 mutations.
We further demonstrated that these two inhibitors function synergistically in eliminating TNBC and HGSOC cells; combining with HS10241 increased DNA double-strand breaks induced by HS10160 in cancer cells; and PARP1 tyrosine (Y)-907 phosphorylation (PARP1 p-Y907) can be an effective biomarker as an indicator of MET-mediated PARPi in HGSOC.
These findings highlight the key components of HR in guiding synthetic lethality with PARP inhibition and support the rationale for utilizing the novel combination of HDACi and PARPi against TNBC in the clinical setting.
It was suggested that miR-206 serves as a target molecule of PARP1 inhibitor combination therapy for BRCA1 wild-type triple-negative breast cancer cells.
In order to better understand how MELK and its inhibition influence TNBC, we verified its anti-proliferative and apoptotic effects in claudin-low TNBC cell lines MDA-MB-231 and SUM-159 using MTS assays and/or trypan blue viability assays together with analysis of PARP cleavage.
Discovery of the molecular signalling molecules that define TNBC heterogeneity has led to the development of targeted agents such as inhibitors of poly (ADP-ribose) polymerase-1 and mTOR and immunomodulatory drugs that are in the early stages of clinical testing.
Although chemotherapy is the main current treatment of this subtype of breast cancer, new agents such as PARP inhibitors, which show promise in the treatment of TNBC, are currently in clinical trials.
Downregulation of miR-221-3p and upregulation of its target gene PARP1 are prognostic biomarkers for triple negative breast cancer patients and associated with poor prognosis.
Furthermore, BET inhibition impaired the ability of TNBC cells to overcome the increase in DNA damage after platinum salts (i.e., CDDP) exposure, leading to massive cell death, and triggered synthetic lethality when combined with PARP inhibitors (i.e., AZD2281).
Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple-negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition.
Immunohistochemistry was used to analyse expression of key HR pathway proteins (ATM, ATR, BRCA1, MDC1, MRE11) and PARP-1 in 100 serous ovarian cancer (SOC) and 100 triple-negative breast cancer (TNBC) tumour samples from Japanese patients.RECIST assessment was used.
<b>Purpose:</b> Both PARP inhibitors (PARPi) and sacituzumab govitecan (IMMU-132) are currently under clinical evaluation in triple-negative breast cancer (TNBC).