Inactivates EGFR, HER2, and HER3 Simultaneously, Making Cancers Less Likely to Develop Resistance to Therapy
This first-in-class compound inhibits cancer cell proliferation. The Epidermal Growth Factor Receptor (EGFR) family members – EGFR, Human Epidermal Growth Factor Receptor-2 (HER2) and Human Epidermal Growth Factor Receptor-3 (HER3) – are well established as proto-oncogenes that play key roles in the initiation and progression of a number of human cancers, including breast cancer lines. These proteins are important targets for therapeutic antibodies and tyrosine kinase inhibitors; however, available chemotherapy approaches, such as Cetuximab, Trastuzumab, and Lapatinib, are unable to target and inactivate all three proteins successfully and at low levels of toxicity. EGFR, HER2 and HER3 have overlapping functions such that inhibition of one or two of these proteins is insufficient. Disulfide bond Disrupting Agents (DDAs) represent a new way of inactivating these oncogenes by downregulating them at the protein level. Researchers at the University of Florida have developed a series of DDAs that may be effective for the treatment of cancers with acquired resistance to inhibitors targeting the EGFR, HER2, and HER3 enzymes, including breast cancers resulting in their degradation. These first-in-class disulfide bond disrupting agents are able to decrease breast cancer cell viability by up to 50 percent and have good activity in cell culture and animal models. In addition to breast and lung tumors, these compounds could be valuable for treating several types of cancers such as salivary gland, head and neck and stomach cancers. Additionally, researchers are successfully applying this compound to lung cancer lines.
Compound that inhibits cell proliferation mediated by EGFR, HER2, and HER3 proteins
- Overcomes deficiency of treating breast cancer with HER2 antibody, which only specifically targets a single receptor HER2 to which 66 to 68 percent of HER2 positive tumors exhibit primary resistance
- Does not damage DNA or RNA
- Inactivates EGFR, HER2, and HER3 simultaneously, making cancers less likely to develop resistance to therapy
- Can be used in combination therapy with conventional cancer chemotherapeutics, such as radiation and surgery, allowing for convenient and versatile administration
These first-in-class anticancer agents could be useful against cell proliferative disorders, specifically breast and lung cancer, both of which are modulated by HER2/HER3/EGFR genes. The compounds use optimal disulfide disrupting agents to disrupt extracellular disulfide bonds associated with the oncogenic functions of EGFR, HER2, and HER3 proteins. Disulfide bond disrupting agents are expected to be toxic to cancer cells dependent on HER2 or EGFR for proliferation and survival but are well tolerated by normal tissues. Unlike cancer treatments using HER2-targeted antibodies (e.g., Trastuzumab and Pertuzumab), this compound simultaneously inactivates EGFR, HER2, and HER3, instead of the single receptor, HER2. This decreases a tumor’s ability to develop primary resistance to the anticancer agent.
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