Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer.
Further large-scale clinical studies are urgently needed for a better designation of PARP inhibitors and Rova-T in the therapeutic algorithm of SCLC patients.
This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors.
SIGNIFICANCE: Our results define previously unrecognized immunomodulatory functions of DDR inhibitors and suggest that adding PARP or CHK1 inhibitors to ICB may enhance treatment efficacy in patients with SCLC.
Following our development of circulating tumor cell patient-derived explants (CDX) as models that faithfully mirror patient disease, here we exploit CDX to examine new therapeutic options for SCLC.<b>Experimental Design:</b> We investigated the efficacy of the PARP inhibitor olaparib alone or in combination with the WEE1 kinase inhibitor AZD1775 in 10 phenotypically distinct SCLC CDX <i>in vivo</i> and/or <i>ex vivo</i> These CDX represent chemosensitive and chemorefractory disease including the first reported paired CDX generated longitudinally before treatment and upon disease progression.<b>Results:</b> There was a heterogeneous depth and duration of response to olaparib/AZD1775 that diminished when tested at disease progression.
PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of radiotherapy in SCLC.<i></i>.
Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, was analyzed using public datasets.
Treatment with cisplatin or PARP inhibitors downregulated SLFN11 and E-cadherin, possibly explaining the rapid development of therapeutic resistance in SCLC.