Lung cancer remains the leading cause of cancer-related deaths in the United States, claiming over 150,000 lives each year. Despite significant progress in the treatment of non-small cell lung cancer (NSCLC)—which accounts for 80-85% of all lung cancer cases—the disease continues to elude effective long-term treatment for many patients.

Resistance to targeted therapies remains a major hurdle, but new research is revealing potential breakthroughs. A study from Moffitt Cancer Center has uncovered how targeting the protein HDAC11 could provide a new avenue for combating this deadly disease, particularly in the face of drug resistance.

Targeting Cancer Stem Cells in NSCLC

Non-small cell lung cancer has been notoriously difficult to treat because of its aggressive nature and tendency to relapse, even after initial successful treatments. This resistance is often linked tot cancer stem cells (CSCs), which are slow-dividing, self-renewing cells that are resistant to conventional therapies.

Since CSCs are responsible for the recurrence and metastasis of lung cancer, eliminating them could be the key to preventing tumor regrowth.

In the Moffitt study, researchers identified HDAC11 as key in maintaining CSC self-renewal. Elevated levels of HDAC11 in lung cancer tissues were correlated with poor prognosis in NSCLC patients. The researchers found that HDAC11 regulates the expression of Sox2, a protein vital to CSC self-renewal. By inhibiting HDAC11 in preclinical models, they were able to significantly reduce Sox2 expression and prevent the self-renewal of lung cancer stem cells.

“This study suggests that targeting HDAC11 could offer a new approach to blocking the self-renewal process of CSCs and inhibiting the progression of NSCLC,” said Srikumar Chellappan, Ph.D., one of the study’s lead authors.

HDAC11 Inhibitors Overcome Drug Resistance

One of the most challenging aspects of treating NSCLC is its resistance to targeted therapies, particularly those aimed at EGFR (epidermal growth factor receptor) mutations. While EGFR inhibitors like erlotinib and gefitinib initially provide clinical benefit, resistance inevitably develops, leading to treatment failure and tumor recurrence. Similarly, chemotherapy drugs like cisplatin, though widely used, have limited efficacy due to the emergence of drug-resistant tumor cells.

The Moffitt team’s discovery that HDAC11 inhibitors could reduce drug resistance offers a promising new approach. In lab experiments, HDAC11 inhibitors, such as FT234 and FT895, were shown to inhibit the growth of NSCLC cells resistant to both chemotherapy and EGFR-targeted therapies. These inhibitors were effective even in lung cancer cells that had developed resistance to commonly used drugs, a significant breakthrough given the challenges faced by current non-small cell lung cancer clinical trials focused on overcoming resistance.

For example, in clinical trials of targeted EGFR therapies, resistance often occurs through secondary mutations, such as the T790M mutation. Researchers at Moffitt found that HDAC11 inhibitors reduced the viability of EGFR-resistant NSCLC cells, suggesting their potential as part of combination therapies in ongoing clinical trials to overcome resistance to these treatments.

“These inhibitors may be able to not only target the cancer stem cells that drive recurrence but also help overcome the resistance mechanisms that have plagued treatment for years,” said Chellappan. As clinical trials continue to explore new combinations of targeted therapies and immunotherapy, HDAC11 inhibitors could become an important addition to the treatment regimen.

Combating the Tumor Microenvironment

In addition to targeting the cancer cells themselves, the tumor microenvironment plays a crucial role in the progression of NSCLC. Cancer-associated fibroblasts (CAFs) are one of the key components of the microenvironment that help tumors resist treatment by secreting growth factors and survival signals. CAFs are known to contribute to resistance in NSCLC and are involved in tumor metastasis.

Remarkably, the HDAC11 inhibitors tested by the Moffitt team showed the ability to reduce cancer cell viability even in the presence of CAFs. In both two-dimensional and three-dimensional co-culture experiments, the inhibitors FT234 and FT895 selectively targeted and eliminated NSCLC cells, even in the presence of CAFs. This result is promising, as it suggests that HDAC11 inhibitors could not only treat the cancer cells directly but also mitigate the supportive role that the tumor microenvironment plays in promoting cancer growth and drug resistance.

The ability of these inhibitors to target both the cancer cells and the surrounding stromal cells represents a significant advantage, especially as clinical trials increasingly focus on the tumor microenvironment as a target for therapy.

Clinical Trials and Future Directions

The potential of HDAC11 inhibitors in NSCLC treatment is still in its early stages, but the preclinical results are compelling. Clinical trials focused on targeting HDAC11 in NSCLC are a logical next step, and researchers are already exploring how these inhibitors might be integrated into existing treatment protocols.

These trials will be crucial in determining the safety and efficacy of HDAC11 inhibitors in human patients, as well as understanding how they can be combined with other therapies to maximize their impact. Currently, clinical trials for NSCLC are testing a range of innovative therapies, from immune checkpoint inhibitors to targeted therapies like EGFR inhibitors and ALK inhibitors. The inclusion of HDAC11 inhibitors in these trials could offer a new weapon in the fight against drug-resistant tumors.

Furthermore, the promise of HDAC11 inhibitors extends beyond NSCLC. The mechanisms uncovered in this study could potentially be applied to other cancers where drug resistance and CSC persistence are major challenges. As more data emerges from clinical trials, the full potential of HDAC11 as a therapeutic target will become clearer.

The findings were reported in the journal Scientific Reports.