Therapeutic resistance remains one of oncology’s most difficult challenges. Cancer cells are genetically and biologically adaptable, and treatment can select for populations that activate alternative pathways to repair damage, continue dividing or evade cell death. As a result, a therapy that produces a strong response at first may eventually lose its effect, allowing the disease to return. “Therapeutic resistance is a main obstacle to achieve effective and durable cancer treatments,” said Dr. Weei-Chin Lin, professor of medicine—hematology and oncology and of molecular and cellular biology at Baylor, who led the study.

The Baylor team focused on TopBP1 because the protein functions as a kind of molecular switchboard. Rather than controlling only one process, TopBP1 coordinates multiple pathways involved in DNA replication, DNA damage responses and cancer-cell survival. The researchers concentrated on a region known as the BRCT7/8 domain, which acts as a docking interface for other regulatory proteins. Interrupting this interface could therefore affect several cancer-promoting systems at once, potentially reducing the ability of malignant cells to compensate when one pathway is blocked.

Among the proteins that interact with TopBP1-BRCT7/8 are MIZ1, a regulator that can suppress the cancer-driving protein MYC; mutant forms of p53, which may acquire functions that actively promote tumor growth; and PLK1 and CIP2A, proteins that support cell division and help cancer cells withstand stress. These interactions give TopBP1-BRCT7/8 an unusually broad influence over tumor biology. The researchers reasoned that a compound capable of selectively disrupting the domain might weaken several lines of defense at the same time.

To find such a compound, the team combined computer-based structural modeling with laboratory screening. Thousands of chemical molecules were evaluated for their ability to fit into the BRCT7/8 binding region and interfere with its interactions. An initial hit, called 3B6, provided a chemical starting point, but it was not sufficiently effective to serve as a promising drug candidate. Researchers chemically modified the compound through multiple rounds of optimization, ultimately producing CS18, which displayed stronger activity in cellular experiments.

The experiments indicated that CS18 affects cancer cells through several connected mechanisms. When the compound binds to TopBP1-BRCT7/8, the activity of MYC and mutant p53 declines, while proteins involved in DNA repair become less effective. At the same time, genes that restrict uncontrolled cell growth become more active. This combination may leave cancer cells unable to repair treatment-induced damage or maintain the signaling programs required for survival, increasing the likelihood that they will undergo programmed cell death.

CS18 produced these effects across a range of malignant cell types, including triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma and acute myeloid leukemia. In the researchers’ tests, the compound was less damaging to noncancerous cells than to cancer cells, although such findings do not establish safety in humans. The broad activity was particularly important because it suggested that TopBP1 inhibition could be relevant across tumors driven by different genetic abnormalities rather than being limited to a single cancer subtype.

The most notable results emerged when CS18 was combined with existing treatments. In cancer models, the compound enhanced the activity of PARP inhibitors, drugs that prevent cells from repairing certain forms of DNA damage. Tumor cells already operating under heavy replication and repair stress may be especially dependent on the remaining repair pathways, making them vulnerable when TopBP1 signaling is also disrupted. CS18 likewise strengthened the effect of osimertinib, a targeted therapy used against certain lung cancers driven by mutant epidermal growth factor receptor, or EGFR.

The combination was particularly effective in cells that had already developed resistance to osimertinib. Adding CS18 restored their sensitivity to the EGFR inhibitor and increased cancer-cell death, indicating that TopBP1 blockade may help dismantle resistance mechanisms rather than simply adding another independent source of toxicity. In animal models, treatment combinations significantly reduced tumor growth without major weight loss or other obvious signs of toxicity during the experiments. However, the results remain preclinical, and further studies will be needed to determine how the compound is absorbed, distributed and metabolized, as well as whether its benefits outweigh potential risks in people.

The researchers describe CS18 as a candidate for further drug development, not as an available cancer treatment. Additional work will need to establish the compound’s precise pharmacology, optimal dosing, long-term safety and effectiveness in more representative tumor models. Clinical trials would ultimately be required to determine whether the strategy can help patients whose cancers resist PARP inhibitors, osimertinib or other therapies. If those studies are successful, targeting TopBP1-BRCT7/8 could lead to combination treatments designed not only to shrink tumors, but also to prevent cancer cells from activating escape routes that enable relapse.

Subject of Research: Cells

Article Title: Development of a structurally distinct TopBP1 inhibitor that enhances PARP blockade and reverses osimertinib resistance

Web References: https://doi.org/10.1126/sciadv.aeg1996; https://www.bcm.edu/people-search/weei-chin-lin-25464

References: Science Advances, DOI: 10.1126/sciadv.aeg1996

Keywords

CS18, TopBP1, cancer drug resistance, cancer therapy, PARP inhibitors, osimertinib, lung cancer, triple-negative breast cancer, ovarian cancer, acute myeloid leukemia, molecular oncology, drug development

The immune microenvironment surrounding tumors is pivotal in either enabling or thwarting cancer progression. Tumors categorized as ‘cold’ maintain an immunosuppressive atmosphere that limits infiltration by cytotoxic T cells and natural killer (NK) cells, key players in tumor eradication. Conversely, ‘hot’ tumors are characterized by substantial immune cell presence and heightened anti-tumor activity. Central to maintaining the ‘cold’ phenotype are Tregs, a subset of immune cells that suppress excessive immune activation but, paradoxically, can be co-opted by tumors to dampen immune attack. SRC-3, a transcriptional coactivator within Tregs, has emerged as an influential modulator of this immunosuppressive function.

In their early work with mouse models of breast and prostate cancer, the researchers employed genetic ablation techniques to delete SRC-3 specifically in Tregs. This intervention transformed these regulatory cells from tumor protectors into potent tumor antagonists. SRC-3 knockout (KO) Tregs showed an enhanced ability to infiltrate tumors and orchestrate the recruitment of effector immune cells capable of destroying cancer cells. Remarkably, this approach elicited robust tumor eradication without inducing the deleterious side effects commonly associated with conventional immunotherapies, such as autoimmunity or systemic toxicity. Moreover, the SRC-3 KO Tregs appeared to confer durable immunity, preventing tumor recurrence in these mouse models.

At the molecular level, SRC-3 KO Tregs exhibited an altered secretion profile, releasing chemokines that act as chemical beacons to attract cytotoxic CD8+ T cells and NK cells into the tumor milieu. Simultaneously, they impeded immune suppressive cells that would otherwise inhibit this anti-tumor assault. This dual mechanism effectively reshaped the tumor microenvironment, turning ‘cold’ tumors into ‘hot’ ones, thereby facilitating an immune-permissive state conducive to tumor destruction.

Encouraged by these promising outcomes, the research team delved deeper, exploring the applicability of SRC-3-deficient Tregs across a broader spectrum of solid tumors, including glioblastoma, melanoma, and lung cancer. These cancers are notorious for their aggressive progression, resistance to therapy, and poor prognosis, highlighting the urgent need for novel immunotherapeutic strategies.

Glioblastoma, an exceptionally lethal brain cancer, is classically associated with an immune-deserted environment, rendering immunotherapies largely ineffective. In mouse models harboring glioblastoma tumors, those lacking SRC-3 in their Tregs demonstrated a remarkable complete suppression of tumor growth. All control animals succumbed to rapidly progressing tumors by 41 days post-implantation, whereas SRC-3 KO mice survived the entire 52-day study duration without detectable tumor burden. Histological analyses revealed substantial infiltration of cytotoxic T cells within tumor tissues, confirming that SRC-3 ablation in Tregs effectively turns the brain tumor microenvironment from immunologically inert into one actively engaged in anti-tumor warfare.

Melanoma, though somewhat more immunologically active than glioblastoma, also leverages Treg-mediated suppression to evade immune elimination. In this context, SRC-3 KO Tregs conferred significant protection against melanoma development in murine models. While every control mouse developed tumors, an impressive 75% of SRC-3 KO mice remained tumor-free and lived beyond 50 days. The elevated presence of tumor-infiltrating lymphocytes in these subjects underscores the enhanced anti-tumor immunity enabled by the SRC-3 knockout in regulatory T cells.

Lung cancer represents another formidable challenge due to its propensity for rapid progression and immune resistance. Studies revealed that both control mice and those with SRC-3 KO Tregs initially exhibited transient tumor regression. Notably, mice with normal Tregs experienced subsequent tumor resurgence followed by mortality within a month. In contrast, animals harboring SRC-3-deficient Tregs achieved sustained tumor clearance, with 60% surviving long-term and exhibiting no signs of tumor recurrence. This longevity was accompanied by amplified infiltration of immune cells within lung tumor tissues, reiterating the capacity of SRC-3 KO Tregs to remodel the tumor microenvironment favorably.

At the immunological mechanism’s core is the capacity of SRC-3 KO Tregs to proliferate extensively and deploy chemokines that attract and activate effector immune cells while simultaneously inhibiting the recruitment or function of immunosuppressive counterparts. This multifaceted mode of action orchestrates a dynamic shift in the local tumor ecosystem, overriding tumor-induced immune evasion strategies.

These collective experimental findings not only underscore the universality of SRC-3’s role in modulating Treg function across diverse tumor types but also affirm the translational potential of targeting SRC-3 as an innovative cancer immunotherapy approach. By harnessing the intrinsic plasticity of Tregs and reprogramming their activity from tumor-supporting to tumor-fighting, this strategy overcomes significant barriers that have historically limited the efficacy of immunotherapies for solid tumors.

Given these advances, Baylor College of Medicine, in collaboration with CoRegen, Inc., is actively pursuing the commercialization and clinical translation potential of SRC-3-targeted therapies. The intellectual property protecting these discoveries has been licensed to CoRegen, reflecting a commitment to advancing these findings from bench to bedside.

Importantly, the absence of severe immune-related adverse events in these preclinical studies suggests that manipulating SRC-3 in Tregs offers a safer alternative to existing immunomodulatory treatments that often provoke autoimmunity. The promising results also hint at the possibility of durable cancer remission with reduced risk of relapse, a longstanding goal in oncology.

Further research is warranted to unravel the detailed molecular pathways through which SRC-3 governs Treg-mediated immunosuppression and to optimize delivery methods for targeted SRC-3 inhibition in human patients. Additionally, expanding trials to encompass other challenging tumor entities may elucidate the broader applicability of this therapeutic paradigm.

In summation, the innovative manipulation of SRC-3 within Tregs represents a transformative leap forward in cancer immunotherapy. By converting immunosuppressive cells into allies of tumor eradication, this approach promises to reshape the landscape of solid tumor treatment, offering hope for more effective, durable, and side-effect-free therapeutic options in the fight against cancer.

Subject of Research: Animals

Article Title: Steroid receptor coactivator 3-deficient regulatory T cells eradicate multiple solid tumors in syngeneic mouse models

News Publication Date: 2-Mar-2026

Web References:

• https://www.pnas.org/doi/10.1073/pnas.2221707120
• https://www.tandfonline.com/doi/full/10.1080/2162402X.2026.2640261#abstract

References:
Han S.J., Lonard D.M., et al. (2026). Steroid receptor coactivator 3-deficient regulatory T cells eradicate multiple solid tumors in syngeneic mouse models. OncoImmunology. https://doi.org/10.1080/2162402X.2026.2640261

Image Credits: Baylor College of Medicine

Keywords: cancer immunotherapy, regulatory T cells, SRC-3, tumor microenvironment, glioblastoma, melanoma, lung cancer, immune suppression, solid tumors, chemokines, immune infiltration, immunomodulation