Targeting a signaling pathway activated by acidic tumor environment restores treatment response to PARP inhibitors in ovarian cancer

UT MD Anderson Research News July 29, 2026

• 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

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.”

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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.