Gilead's PI3K Inhibitor Zydelig Shows Promise as a Novel Therapeutic Strategy for Triple-Negative Breast Cancer by Targeting Stromal Fibroblasts

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Triple-negative breast cancer (TNBC) is difficult to treat because it lacks three common drug targets. Currently, a research team at the University of Sussex in the United Kingdom has identified a target within the tumor microenvironment rather than directly targeting the tumor itself, and determined that an already marketed blood cancer drug holds potential for treating TNBC.

Researchers have found that targeting the PI3K pathway in healthy tissues surrounding tumor cells with Zydelig (idelalisib), an approved anticancer drug from Gilead Sciences, can slow the growth of triple-negative breast cancer (TNBC) and reduce tumor metastasis in mouse models. These findings were recently published in the prestigious international medical journal Journal of Clinical Investigation. The article is titled: PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression.

Zydelig was approved by the U.S. FDA in July 2014 as the first phosphoinositide 3-kinase (PI3K) inhibitor approved for the treatment of B-cell malignancies, exhibiting high selectivity for the PI3Kδ isoform. Activation of the PI3K/AKT/mTOR pathway is a known factor contributing to the development and treatment resistance of various cancer types. In 2019, the FDA also approved Novartis’ PI3K inhibitor Piqray (alpelisib, targeting PI3Kα) in combination with AstraZeneca’s Faslodex for the treatment of advanced HR+/HER2- breast cancer with PIK3CA mutations.

After analyzing samples from patients with triple-negative breast cancer (TNBC), researchers linked high levels of PIK3Cδ in fibroblasts, the most prominent cells in the tumor microenvironment (f-PIK3Cδ), to poor patient survival. Cell lines cultured in laboratory dishes also showed increased TNBC invasiveness, although the tumor cells themselves did not exhibit changes in PIK3Cδ protein levels. Through genetic and pharmacological gain-of-function and loss-of-function assays, researchers confirmed the role of f-PIK3Cδ in cell invasion. Combined secretomic and transcriptomic analyses revealed that f-PIK3Cδ exerts pro-tumorigenic effects via paracrine mechanisms. Inhibition of f-PIK3Cδ promotes the secretion of factors such as PLGF and BDNF, leading to upregulated NR4A1 expression in TNBC cells and thereby exerting tumor-suppressive effects.

To validate the efficacy of PIK3Cδ inhibition, the research team tested Zydelig in two triple-negative breast cancer (TNBC) mouse models and observed a significant slowdown in tumor growth following treatment. Compared with the control group, animals treated with Zydelig also exhibited a marked reduction in the number of pulmonary metastatic nodules. Notably, in an orthotopic breast cancer mouse model, PIK3Cδ inhibition slowed tumor growth only after fibroblast inoculation, highlighting the role of fibroblast-derived PIK3Cδ (f-PIK3Cδ) in tumor progression. Similar results were observed in the MMTV-PyMT transgenic breast cancer mouse model, where the reduction in tumor metastasis further underscored the potential immune-independent effects of PIK3Cδ inhibition. Finally, through analysis of breast cancer patient cohorts and The Cancer Genome Atlas (TCGA) dataset, researchers identified f-PIK3Cδ (at both protein and mRNA levels) as an independent prognostic factor and a potential therapeutic target for TNBC.

The research team hopes that this discovery will spur industry interest in evaluating Zydelig or other PI3Kδ inhibitors for the treatment of triple-negative breast cancer (TNBC) in clinical trials. Corresponding author Georgios Giamas stated, “Our findings suggest that repurposing already approved drugs as PI3Kδ inhibitors holds promise for halting TNBC progression. Given that these agents are already on the market, clinical trials can be initiated immediately to further investigate their potential in treating TNBC.”

Currently, other research teams are also turning to existing drugs in search of inspiration for addressing triple-negative breast cancer (TNBC). In another new study published in Science Translational Medicine (article title: Targeting MYCN-expressing triple-negative breast cancer with BET and MEK inhibitors), a research team from Vanderbilt University identified the role of the MYCN oncogene in TNBC. MYCN is a transcription factor belonging to the MYC family, whose members regulate the expression of genes involved in cell growth, proliferation, metabolism, and survival. Aberrant expression of MYCN has been observed in neuronal or neuroendocrine tumors.

The research team at Vanderbilt University discovered that MYCN is also overexpressed in triple-negative breast cancer (TNBC), with higher expression levels observed in cases resistant to chemotherapy. Although strategies directly targeting MYC have not been successful, the team found that the combined use of BET and MEK inhibitors can exert an indirect effect.

Researchers reported that in patient-derived xenograft mouse models prepared from tumors of TNBC patients expressing MYCN, the addition of Novartis’ approved MEK inhibitor Mekinist to a BET inhibitor—either Incyte’s INCB054329 or another drug named JQ1—in combination therapy resulted in significant slowing of tumor growth in mice.

BET Inhibitors and MEK Inhibitors in Combination Therapy Can Suppress Tumor Growth

Breast cancer is the most common type of cancer in women, with over 2 million new cases diagnosed globally each year. Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancers and is more prevalent in women under the age of 50 compared to other subtypes. TNBC is specifically defined by the negative expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). It progresses rapidly, carries a very poor prognosis, and has a 5-year survival rate of less than 15%. TNBC does not respond to hormonal therapy or HER2-targeted therapy, leaving treatment options severely limited and primarily reliant on chemotherapy. Metastatic TNBC is among the most aggressive and difficult-to-treat forms of breast cancer.

In recent years, progress has been made in the development of new drugs for triple-negative breast cancer (TNBC). In 2019, Roche’s Tecentriq in combination with chemotherapy was approved, becoming the first cancer immunotherapy regimen for the treatment of PD-L1-positive metastatic TNBC. Currently, the company is conducting multiple clinical trials to evaluate Tecentriq for the treatment of early-stage and advanced TNBC.

Immunomedics’ first-in-class antibody-drug conjugate, sacituzumab govitecan, is under regulatory review in the United States for third-line treatment of metastatic triple-negative breast cancer (TNBC). This innovative TROP-2-targeted therapy demonstrated an overall response rate of 34% in Phase II clinical trials. The confirmatory Phase III trial is currently ongoing.

Furthermore, Merck’s Keytruda has also demonstrated robust efficacy in the neoadjuvant/adjuvant treatment of early-stage triple-negative breast cancer (TNBC), significantly improving pathological response rates in Phase III clinical trials. In February this year, a Phase III clinical study evaluating Keytruda combined with chemotherapy as first-line treatment for PD-L1-positive TNBC met one of its primary endpoints, significantly prolonging progression-free survival.

Reference Source: How Gilead's blood cancer med Zydelig might also address triple-negative breast cancer