The Combination of the PARP Inhibitor Olaparib and the WEE1 Inhibitor AZD1775 as a New Therapeutic Option for Small Cell Lung Cancer

Abstract

Introduced in 1987, platinum-based chemotherapy remains standard of care for small cell lung cancer (SCLC), a most aggressive, recalcitrant tumor. Prominent barriers to progress are paucity of tumor tissue to identify drug targets and patient-relevant models to interrogate novel therapies. 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. 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 and/or These CDX represent chemosensitive and chemorefractory disease including the first reported paired CDX generated longitudinally before treatment and upon disease progression. There was a heterogeneous depth and duration of response to olaparib/AZD1775 that diminished when tested at disease progression. However, efficacy of this combination consistently exceeded that of cisplatin/etoposide, with cures in one CDX model. Genomic and protein analyses revealed defects in homologous recombination repair genes and oncogenes that induce replication stress (such as MYC family members), predisposed CDX to combined olaparib/AZD1775 sensitivity, although universal predictors of response were not noted. These preclinical data provide a strong rationale to trial this combination in the clinic informed by prevalent, readily accessed circulating tumor cell-based biomarkers. New therapies will be evaluated in SCLC patients after first-line chemotherapy, and our data suggest that the combination of olaparib/AZD1775 should be used as early as possible and before disease relapse. .

Wee1 Inhibition Enhances the Anti-Tumor Effects of Capecitabine in Preclinical Models of Triple-Negative Breast Cancer

“…In addition to chemotherapy combinations, AZD1775 has shown efficacy when combined with other small molecules. Olaparib, in combination with AZD1775, demonstrated enhanced anti-tumor effects in both small cell lung and ovarian cancers [20,21]. These studies demonstrated a synergistic anti-proliferative effect, and an enhancement in apoptosis and decreases in p-CDC2 in AZD1775-treated ovarian cancer cells that was maintained in the combination.…”

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

“…Preliminary analysis from this ongoing study revealed that basal protein PARylation distinguishes sensitive CDX models from both intermediate and resistant models, while PARylation, like SLFN11 expression, appears to decrease with treatment and the develop-ment of resistance (72). A similar CDX-based approach investigating the combination of olaparib with or without the WEE1 inhibitor adavosertib (AZD1775) identified multiple additional biomarker candidates, including inducers and markers of replication stress, such as MYC-family proteins, phospho-RPA, and cyclinE1 (73). Given the relative dearth of tissue available in SCLC and other tumors not commonly managed via surgical resection, approaches such as these may shape the next era of biomarker discovery for PARP inhibitors and beyond.…”

“…This overarching mechanism of HRR restoration has been highlighted in multiple preclinical PDX studies of PARP inhibition in TNBC (15,(80)(81)(82), where functionality of HRR in virtually all cases was implied by the presence of RAD51 foci in untreated tumor samples, suggesting this could represent a useful clinical biomarker for PARP inhibitor response and/or resistance. Emerging data also suggest that these olaparibresistant cancer models can be resensitized to olaparib when combined with a WEE1 inhibitor or an ATR inhibitor (67,73,(83)(84)(85). Preclinical studies suggest that PARP inhibitor-resistant, BRCA-deficient cells have an increased reliance on ATR signaling for fork stabilization (83,84), while synthetic lethal screens identified ATR as a target that was able to overcome PARP inhibitor resistance, leading to early-phase clinical trials combining ATR and PARP inhibitors (NCT02723864, NCT03462342, NCT03682289, NCT02576444; ref.…”

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

“…Although small‐cell lung cancer (SCLC) accounts for only 15% to 20% of all lung cancer cases, 60% of patients have extrathoracic metastases at the time of diagnosis, and few of them can survive more than 1 year, which gives a major challenge for the health care system . Despite significant progress has been done, there are still a few new small molecular drugs and biologics that have benefited patients with SCLC markedly . Thus, development of novel drugs for SCLC treatment is urgent.…”

“…2,3 Despite significant progress has been done, there are still a few new small molecular drugs and biologics that have benefited patients with SCLC markedly. 4 Thus, development of novel drugs for SCLC treatment is urgent. p53, a well-known tumor suppressor, is closely associated with diverse cellular signals involved in cell cycle, cell apoptosis, cell metabolism, and so on.…”