New Targets Emerge for Aggressive Small Cell Lung Cancer

While there have been notable breakthroughs in recent years in the treatment of small cell lung cancer (SCLC), there is still a relative dearth of targeted therapies for this aggressive subtype. Researchers have sought to address this need by developing cell-permeable, orally bioavailable macrocyclic peptides.

In an interview with Targeted Oncology®, Matthew Oser, MD, associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, discusses this research and its implications for future research and development.

Targeted Oncology: What are some of the unmet needs that prompted this line of research?

Matthew Oser, MD: Small cell lung cancer, which makes up about 13% of lung cancers, is driven primarily by loss-of-function mutations in tumor suppressor genes with near universal loss of RB1 and TP53. It’s been challenging to identify targeted strategies to exploit the loss of tumor suppressor genes. More recently, there has been a lot of excitement with positive clinical data in terms of cell surface targets in SCLC. But this study was a strategy to think about what is different in a cancer cell with loss of tumor suppressor genes, RB1 and TP53, and how we might exploit that.

What were the objectives of this study? What were your findings?

This was a collaboration with Circle Pharma, which had, based on evidence dating to the late 1990s, developed macrocycles to target cyclins. A macrocycle is a cyclic peptide, and Circle Pharma had optimized the chemistry for these macrocycles to be dosed orally. What the cyclic peptide does is block the ability of cyclins, which drive the cell cycle, to interact with their substrates through interfering with a cyclin-mediated RxL interaction of their substrates.

E2F drives the cell cycle, but too much E2F activity can be bad for cells, so that can actually induce apoptosis. One of the mechanisms that cancer cells use to really keep E2F activity in check is by cyclin A binding to E2F and dampening its activity. Research from the late 90s showed that potentially, if you disrupt that interaction, this may exploit cancers with high E2F activity and kill those cells. So that was the motivation to build these macrocycles with tractable therapeutics that could block this interaction. The objective was to understand how these macrocycles targeting cyclin A and B worked and if there is activity. Through that, we discovered that cancer cells with a compromised G1-S checkpoint and consequently high E2F activity were highly sensitive to macrocycles targeting cyclin A and cyclin B. We found some unexpected mechanisms by which macrocycles that target cyclin A and cyclin B dysregulate the cell cycle to induce apoptosis and defined how they kill cancer cells with dysregulated E2F activity, such as small cell lung cancer.

What are the clinical implications of these findings?

I think this is an exciting approach with a potentially high therapeutic window. We found that cancer cells with high E2F activity were exquisitely sensitive to this therapeutic approach of blocking cyclin A and cyclin B's RxL interactions with their substrates, whereas insensitive cancer lines with lower E2F activity or normal cells were relatively insensitive, and with hundred- to thousand-fold differences in therapeutic windows. We think this is a potential strategy that can be utilized for cancers with high E2F activity. These are cancers with dysregulated G1-S checkpoints. This may be like in small cell lung cancer from RB1 and TP53 loss. But in other cancers, there are other mechanisms that could be at play to disrupt the G1-S checkpoint, resulting in high E2F activity that would similarly make the cancer susceptible to these macrocycle therapeutics targeting cyclin A and cyclin B.

What questions do you still have based on this research?

Mechanistically, I think one of the really unexpected findings is these macrocycles ultimately induced the formation of a complex of cyclin B with CDK2 to promote apoptosis. Cyclin B normally binds CDK1 in mitosis. These macrocycles induced an aberrant complex of cyclin B and CDK2 and were absolutely required to induce cell death in mitosis through activation of the spindle assembly checkpoint. So, we understand why cyclin B activity increased by treating cells with the drug. We still have questions about understanding the full mechanism of action of why, apparently, CDK2 gets recruited to cyclin B, and then also other questions about whether other RxL-mediated interactions that, when disrupted, contribute to the efficacy.

We tested these compounds in cell line xenograft models and then also in patient-derived xenograft models that were made from patients who were resistant to first-line chemotherapy, and we saw really profound activity in really all models that we tested. But these were all in immunodeficient mice, and so these mice didn't have a full adaptive immune system with T cells and B cells. So, another question, given lots of exciting data in small cell lung cancer from the last 5 years or so with immune checkpoint blockades and newer agents such as the DLL3-targeted bispecific T-cell engager tarlatamab (Imdelltra) are there opportunities for combination strategies? These compounds do induce DNA damage, and potentially, is that something that could stimulate an immune response on its own? We don't know.

REFERENCE:

Singh S, Gleason CE, Fang M, et al. Targeting G1–S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors. Nature. 2025;646(8085):734-735. doi:10.1038/s41586-025-09433-w