Preclinical studies with ONC201/TIC10 and lurbinectedin as a novel combination therapy in small cell lung cancer
Nicholas R Liguori1,2, Ashley Sanchez Sevilla Uruchurtu2,3, Leiqing Zhang2,3
1Temple University, Lewis Katz School of Medicine Philadelphia, Pennsylvania 19140, USA.
Abstract:
The American Cancer Society estimates that ~15% of all lung cancers are categorized as small cell lung cancer (SCLC) with an overall five-year survival rate of less than 7%. Due to disease aggressiveness, more other malignancies, the standard of care is based on clinical efficacy rather than helpful biomarkers. Lurbinectedin is a small molecule RNA polymerase II inhibitor that binds the minor groove of DNA to induce double-strand breaks. Lurbinectedin has efficacy towards SCLC cells at sub-nM concentration and received accelerated FDA approval in 2020 for metastatic SCLC that progressed on platinum-based therapy. ONC201/TIC10 is a TRAIL pathway-inducing compound that with demonstrated clinical efficacy in H3K27M-mutated diffuse midline glioma and neuroendocrine tumors, in early phase clinical trials. We hypothesized that combining ONC201 and lurbinectedin may yield synergistic and targeted killing of SCLC cells. SCLC cell lines H1048, H1105, H1882, and H1417 were treated with ONC201 and lurbinectedin and cell viability was determined using a CellTiter-Glo assay using varying drug concentrations. Synergistic growth inhibition of SCLC cells was noted with combination of ONC201 and lurbinectedin. Induction of the integrated stress response mediator ATF4 and CHOP was observed with ONC201 and lurbinectedin along with induction of PARP cleavage indicative of apoptosis in response to cellular stress. Additionally, SCLC lines treated with the combination therapy displayed increased DNA breakage-related proteins such as phosphorylated Chk-1, Wee1 and γ-H2AX. Combination index revealed the most potent synergy occurred at the concentrations of 0.16 μM ONC201 and 0.05 nM lurbinectedin in the H1048 cell line, demonstrating highly efficient and selective killing of these tumor cells in vitro. While these therapies showed potency against the cell lines derived from SCLC patients, it is noteworthy that the combination showed significantly less toxicity to healthy human lung epithelial cells. Future studies could explore the combination of ONC201 and lurbinectedin in SCLC cell lines, SCLC patient-derived organoids, other tumor types, including in vivo studies and clinical translation.
Insights
Combining ONC201 and lurbinectedin shows synergistic killing of small cell lung cancer (SCLC) cells. This novel combination therapy effectively targets SCLC with reduced toxicity to healthy lung cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Small cell lung cancer (SCLC) has a poor prognosis, with limited treatment options and low survival rates.
- Current SCLC treatments lack targeted biomarkers, necessitating therapies focused on clinical efficacy.
- Lurbinectedin and ONC201 are emerging therapeutics with distinct mechanisms of action against cancer cells.
Purpose of the Study:
- To investigate the potential synergistic anti-cancer effects of combining ONC201 and lurbinectedin in SCLC.
- To evaluate the efficacy and safety of this combination therapy in preclinical SCLC models.
Main Methods:
- SCLC cell lines were treated with varying concentrations of ONC201 and lurbinectedin.
- Cell viability was assessed using CellTiter-Glo assays.
- Molecular markers of apoptosis, DNA damage, and stress response were analyzed.
Main Results:
- The combination of ONC201 and lurbinectedin demonstrated synergistic growth inhibition across multiple SCLC cell lines.
- Combination therapy induced apoptosis, increased DNA damage markers (e.g., γ-H2AX), and activated stress response pathways (ATF4, CHOP).
- The most potent synergy was observed at specific concentrations, showing highly efficient and selective killing of SCLC cells with minimal toxicity to healthy lung cells.
Conclusions:
- Combination therapy with ONC201 and lurbinectedin exhibits significant preclinical efficacy against SCLC.
- The synergistic effect is mediated through enhanced apoptosis and DNA damage induction.
- This combination represents a promising therapeutic strategy for SCLC, warranting further investigation in clinical trials.
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