Antibody Cocktail Blocks Growth of Drug-Resistant Lung Tumors in Mouse Model

Cancer researchers developed a cocktail of three monoclonal antibodies that was able to halt drug-resistant tumor growth in a mouse xenograft lung cancer model.

Lung cancer patients with primary epidermal growth factor receptor (EGFR) mutations usually respond well to treatment with targeted kinase inhibitors, but almost always develop drug acquire resistance, often due to a second-site mutation (T790M). Clinical trials have tested the ability of a monoclonal antibody (mAb) to EGFR but failed to demonstrate any survival benefits despite the fact that the mAB should have blocked activation of the mutated receptor.

Investigators at the Weizmann Institute of Science (Rehovot, Israel) traced the reason for this failure. By using cell lines with the T790M mutation, they discovered that prolonged exposure to mAbs against only the EGFR triggered molecular network rewiring by (i) stimulating the extracellular signal–regulated kinase (ERK) pathway; (ii) inducing the transcription of HER2 (human epidermal growth factor receptor 2) and HER3, which encode other members of the EGFR family, and the gene encoding HGF (hepatocyte growth factor), which is the ligand for the receptor tyrosine kinase MET, a molecule often expressed in metastatic cancers.

To counter the emergence of this new pathway, the investigators developed mAbs against HER2 and HER3. They reported in the June 2, 2015, online edition of the journal Science Signaling that supplementing the EGFR-specific mAb with those targeting HER2 and HER3 suppressed the compensatory feedback loops that had developed in cultured lung cancer cells. The triple mAb combination targeting all three receptors prevented the activation of ERK, accelerated the degradation of the receptors and inhibited the proliferation of tumor cells but not of normal cells. Furthermore, treatment with the antibody cocktail markedly reduced the growth of tumors in mice xenografted with cells that were resistant to combined treatment with erlotinib and the single function-blocking EGFR mAb.

"Treatment by blocking a single target can cause a feedback loop that ultimately leads to a resurgence of the cancer," said senior author Dr. Yosef Yarden, professor of molecular cell biology at the Weizmann Institute of Science. "If we can predict how the cancer cell will react when we block the growth signals it needs to continue proliferating, we can take preemptive steps to prevent this from happening."

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Weizmann Institute of Science