Study Links PAK5 to Poor Outcomes and Drug Resistance in HER2-Positive Breast Cancer

Researchers have identified p21-activated kinase 5 (PAK5) as a potential therapeutic target for overcoming trastuzumab emtansine (T-DM1, Kadcyla; Genentech) resistance in human epidermal growth factor receptor-positive (HER2+) breast cancer (BC), according to study findings published in Cell Death & Disease.1

3D illustration of trastuzumab molecule | Image Credit: © LASZLO - stock.adobe.com

In 2023, approximately 290,000 women were diagnosed with HER2+ BC, which represents 20% of all BC diagnoses. With a high chance of recurrence, it is a difficult disease to treat, particularly for individuals who still have invasive disease following neoadjuvant therapy. Innovative HER2-targeted treatments, such as the antibody drug conjugate T-DM1, have greatly changed outcomes for patients. It was approved by the FDA in 2019 for the adjuvant treatment of patients with HER2+ early BC who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.²

Similar to other treatments, resistance remains a challenge for some patients, barring them from optimal health outcomes. In the study, the researchers point specifically to nuclear HER2 (N-HER2) as a driver of significant proliferation and resistance to HER2-targeted treatments, like trastuzumab, and to worse outcomes in patients with BC. However, the reasons behind this weren’t well understood. This study shows that high levels of another protein, PAK5, are associated with both resistance to HER2-targeted therapy and poorer patient outcomes.¹

To better understand how PAK5 affects breast cancer, researchers measured its levels in 102 tumor samples using lab techniques. They found that higher PAK5 levels were linked to more advanced cancer and HER2-positive status. When they looked at HER2-positive BC cell lines, they noticed that the JIMT-1 cells—which are naturally resistant to trastuzumab—had much higher PAK5 levels than cells that respond well to the drug.¹

In tissue samples from 58 patients with HER2-positive BC treated with trastuzumab, those with high PAK5 expression were more likely to be resistant to the treatment. These patients also had worse overall survival and disease-free survival. Lab tests showed that increasing PAK5 in trastuzumab-sensitive cells made them less responsive to both trastuzumab and lapatinib (Tykerb; GSK), another targeted therapy. Alternatively, lowering PAK5 levels in resistant cells made them more sensitive to both drugs.¹

The researchers also found that PAK5 affects another molecule, METTL14, by adding a chemical tag to it. This increases the stability of a long non-coding RNA called MALAT1, which then prevents the breakdown of N-HER2. As a result, N-HER2 builds up in the cells. Additionally, HER2 itself helps boost the levels of PAK5 and MALAT1, creating a feedback loop that further strengthens this resistance mechanism.¹

The study shows that PAK5 plays a key role in making HER2-positive breast cancer cells resistant to treatment and could be a promising target for new therapies. Targeting PAK5 may not only help overcome resistance to drugs like trastuzumab and lapatinib but also improve outcomes for patients with HER2-positive breast cancer who currently have limited options after standard therapies fail.

REFERENCES

1. Zhao X, Li Y, Zhang H, et al. PAK5 promotes the trastuzumab resistance by increasing HER2 nuclear accumulation in HER2-positive breast cancer. Cell Death & Disease. April 21, 2025. Doi:10.1038/s41419-025-07657-2

2. Adjuvant trastuzumab emtansine improves invasive disease-free survival in patients with HER2+ early breast cancer. Pharmacy Times. January 24, 2025. Accessed April 22, 2025. https://www.pharmacytimes.com/view/adjuvant-trastuzumab-emtansine-improves-invasive-disease-free-survival-in-patients-with-her2-early-breast-cancer