• PARP inhibitors are among the most widely used therapies for ovarian cancer, but their long-term effectiveness is limited by acquired resistance 

• Researchers found a signaling pathway activated by the tumor microenvironment was a major driver of resistance, and blocking the pathway was able to resensitize tumors 

• The pathway was activated because the tumor microenvironment is acidic, which is common in several tumor types, demonstrating broad potential for this approach  

• Several drugs targeting this pathway already are in development, supporting potential future clinical investigation 

HOUSTON, JULY 29, 2026 ― Researchers at The University of Texas MD Anderson Cancer Center have discovered a promising strategy to overcome PARP inhibitor resistance in ovarian cancer, one of the most common barriers to the long-term effectiveness of this widely used treatment.  

Targeting a signaling pathway activated by the acidic tumor microenvironment restored sensitivity to PARP inhibitors in preclinical models, suggesting a potential new therapeutic strategy for overcoming acquired resistance. The study, published in Cancer Research, was led by Rugang Zhang, Ph.D., professor and chair of Experimental Therapeutics, and Kaixin Cheng, Ph.D., postdoctoral fellow in the Rugang Zhang Laboratory. 

“PARP inhibitors have transformed treatment for many patients with ovarian cancer, but resistance often limits their long-term effectiveness,” Zhang said. “This study revealed that the tumor microenvironment plays a critical role in driving treatment resistance and suggests a potential strategy for restoring sensitivity to PARP inhibitors and extending their benefit for patients.” 

How does an acidic microenvironment help tumors evade treatment? 

Acidity is a hallmark of many tumors, which often accumulate acid due to abnormal metabolism and poor blood flow. While tumor acidity has long been associated with resistance to cancer therapies, its effects on PARP inhibitor response remained unclear. 

PARP inhibitors block a key DNA repair pathway that cancer cells rely on for survival. These therapies are particularly effective in ovarian cancers that already have defects in DNA repair, such as tumors with BRCA mutations. However, many tumors eventually develop resistance to PARP inhibitors, leaving patients with fewer effective treatment options. 

In this study, researchers found that ovarian cancer cells exposed to acidic conditions became significantly less sensitive to PARP inhibitors. Acidic environments activated a signaling network involving ERK, p300 and PARP1 – proteins that collectively regulate cellular signaling, gene activity and DNA repair. Activation of this pathway reduced PARP trapping, a process in which PARP inhibitors lock PARP enzymes at sites of DNA damage to prevent repair. By reducing PARP trapping, this pathway decreases the effectiveness of these drugs. 

How does targeting this signaling pathway reverse treatment resistance? 

A large-scale CRISPR genetic screen identified p300 as a critical driver of the resistance pathway activated by tumor acidity. Researchers discovered that p300 adds a small chemical tag to PARP1 through a process called acetylation. This modification helped cancer cells avoid the DNA damage caused by PARP inhibitors.  

Disrupting this process with p300 inhibitors restored sensitivity to PARP inhibitors in ovarian cancer cells, leading to stronger antitumor responses across multiple preclinical models, including those with acquired PARP inhibitor resistance. 

The findings also suggest PARP1 acetylation and ERK activation may have potential as biomarkers of treatment resistance. Analysis of tumor samples from ovarian cancer patients treated with PARP inhibitors found that tumors with higher levels of activated ERK and acetylated PARP1 were more likely to be resistant to treatment and were associated with poorer outcomes.  

What’s next for this research? 

This study provides a strong rationale for further research on p300 inhibitors in ovarian cancer treatment. Future clinical trials could evaluate whether combining p300 inhibitors with PARP inhibitors could overcome treatment resistance or perhaps improve outcomes for patients who typically do not benefit from PARP inhibitors. 

Several p300 inhibitors, including IACS-16559, an agent developed by UT MD Anderson’s Therapeutics Discovery division, are being evaluated preclinically or are in early-stage clinical development, supporting the potential for further investigation of this therapeutic strategy. 

Additional research is needed to determine whether PARP1 acetylation and ERK activation could serve as biomarkers for predicting treatment response. Future studies also may identify additional mechanisms within the tumor microenvironment that drive treatment resistance, further expanding opportunities for therapeutic intervention. 

“One of the most striking findings was that the same amount of treatment was still reaching cancer cells, meaning the problem was not drug delivery,” Cheng said. “These findings suggest that the acidic tumor microenvironment may be an important therapeutic target alongside the cancer cell.” 

*** 

This research was supported by the National Institutes of Health, the U.S. Department of Defense, the Cancer Prevention and Research Institute of Texas (CPRIT), the Ovarian Cancer Research Alliance, and institutional support from UT MD Anderson and The Wistar Institute. For a full list of collaborating authors, disclosures and funding sources, see the full paper in Cancer Research.

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-26-0834

Cancer, a disease notorious for its intricacies and ability to evade treatment, often exhibits aberrant biological markers. One such marker is P-cadherin, a cell adhesion protein that is overexpressed in a myriad of malignant tumors. Its presence on the surface of cancer cells renders it an attractive target for therapeutic interventions. Researchers have long sought ways to exploit this overexpression to enhance the specificity and efficacy of drug delivery systems, and this study marks a pivotal advancement in that pursuit.

In their investigation, researchers from the University of California, Davis, led by graduate students Bin Xie and Shipeng Xu, under the guidance of Professor Sanjeevi Sivasankar, conducted meticulous experiments to unravel the binding dynamics of an antibody known as CQY684 with P-cadherin. Their methodology was rigorous, employing sophisticated biophysical techniques to observe the interactions at a molecular level, thereby establishing a clear pathway of antibody attachment and subsequent cellular uptake.

The study provided an exciting revelation: when CQY684 binds to P-cadherin, it stabilizes the protein in a unique conformation known as the X-dimer. Unlike the standard dimer configuration, this X-dimer is poised to initiate a series of cellular events that ultimately result in the internalization of the antibody-protein-drug complex. This finding not only sheds light on the fundamental biology of cell adhesion but also opens avenues for designing more effective targeting strategies for drug delivery.

The mechanism described in the study operates through a chemical signaling process initiated by the conversion to the X-dimer. Upon stabilization, this dimer activates intracellular signaling cascades that lead to a phenomenon known as endocytosis, where a portion of the cell membrane invaginates to form a vesicle, effectively ‘sucking’ the P-cadherin/antibody/drug complex into the cell. This intricate process is not just a fascinating biochemical dance; it has profound implications for how we can deliver therapeutic agents to cancer cells more efficiently.

The ultimate destination of the internalized complex is the lysosome, a cellular organelle responsible for degradation and recycling of biomolecules. Understanding this pathway allows researchers to strategically design drugs that can be packaged with antibodies targeting P-cadherin, ensuring that treatments are not only localized but also potent. By utilizing P-cadherin as a vessel for drug transport, oncologists may be able to increase the therapeutic index of anticancer drugs while minimizing systemic toxicity.

The implications of this work extend beyond just the immediate findings. The study lays the groundwork for future research that could harness this mechanism to tackle a wider array of diseases where cell adhesion molecules play a critical role. For instance, the insights into the P-cadherin signaling and endocytosis could inspire novel therapeutic approaches not only in oncology but in autoimmune diseases, where targeted delivery to specific cell types could change the treatment paradigm.

As the researchers conclude, the established "outside-in" signaling mechanism represents a critical addition to our understanding of cellular dynamics and drug delivery strategies. It posits an innovative model of how antibodies can be engineered to enhance cellular uptake of therapeutic agents, which could lead to advanced treatments that are better tailored to the complex biology of cancer. With continued exploration and development, the therapeutic potential of these findings could revolutionize the landscape of cancer treatment.

In this era where traditional pharmacotherapy is increasingly complemented by targeted approaches, studies like this mark essential steps toward overcoming the many barriers that prevent effective cancer therapies. The research community will undoubtedly keep a close eye on follow-up studies stemming from this groundbreaking work, as they could hold the keys to more sophisticated and humane cancer therapeutics.

Ultimately, the pursuit of efficacious cancer treatments continues unabated. Researchers remain optimistic that with an enhanced understanding of the cellular mechanisms involved in drug delivery, the next generation of cancer therapies will not only be more effective but also offer improved safety profiles for patients. The cascading effects of this research could translate into a future where targeted therapies become the norm rather than the exception, providing a beacon of hope for patients battling malignancies.

As scientists continue to delve deeper into the nuances of cell signaling, the horizon looks promising, with a wealth of opportunities for innovation in drug development. The marriage of biophysics and biomedical engineering showcased in this study serves as a testament to collaborative interdisciplinary efforts that are essential for tackling complex health challenges. With perseverance and ingenuity, the field stands ready to unravel more such mechanisms, fostering the evolution of cancer treatment methodologies that resonate with efficacy.

Subject of Research: Cells
Article Title: Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody
News Publication Date: 29-Jan-2025
Web References: Link to Nature Communications Article
References: Link to DOI
Image Credits: University of California, Davis

Keywords: Cancer cells, Antibodies, Targeted drug delivery, Surface proteins, Biomedical engineering