Drug synergy demonstrated between EGFR inhibitors and CRIPTO antagonist ALK4L75A-Fc in patient-derived triple-negative breast cancer organoids

Breast cancer is diagnosed in approximately 2.3 million women and takes the lives of
about 685,000 women each year (Alam 2022). Among the breast cancer subtypes, triple negative breast cancer (TNBC) has the worst prognosis, with a five-year mortality rate of 40% (Yin 2020). As TNBC tumors lack three common therapeutic targets present in other breast cancers—estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2—treatment options are scarce (Alam 2022). One proposed TNBC therapeutic, epidermal growth factor receptor (EGFR) inhibitors, works well in other cancers, but is clinically ineffective in breast cancer (Li 2022). We hypothesized that a breast cancer-specific mechanism could be altering EGFR levels, leading to the clinical failure of EGFR inhibitors. We explored the effect of CRIPTO (teratocarcinoma-derived growth factor, TDGF1) on EGFR and found that CRIPTO increased EGFR levels in TNBC cells. We proposed that a combination therapy targeting CRIPTO and EGFR could be effective in TNBC patients. We assessed the synergy between various FDA-approved EGFR inhibitors and a novel, genetically-engineered chemotherapeutic agent (ALK4-Fc) in multiple patient-derived TNBC organoids. Given the promising results of these preclinical studies, this combination therapy could remedy the paucity of TNBC treatment options.