Abstract
Abstract BRaf and MEK targeting drugs result in impressive tumor response rates in melanoma cancer patients, but adaptive resistance hampers the clinical benefit by limiting durability of these drugs. We used a panel of melanoma and colorectal-derived cell lines harboring activating BRaf mutations to evaluate the role of ErbB3 signaling in mediating resistance to BRaf and MEK inhibitors. Treatment of cells with vemurafenib or trametinib results in upregulation of ErbB3 cell surface levels. These cells become hypersensitive to the effects of the ErbB3 ligand NRG; addition of NRG results in a several-fold increase of phosphorylation of ErbB3 (pErbB3) and AKT (pAKT) relative to drug-untreated cells. This effect can be reverted by KTN3379- an anti-ErbB3 monoclonal antibody in clinical development- with low nanomolar IC50 values. NRG can also rescue the cytotoxic effects of BRaf or MEK inhibition making these cells resistant to treatment with BRaf or MEK inhibitors. Addition of KTN3379 re-sensitizes the tumor cells to the antiproliferative effects of vemurafenib and trametinib. Moreover, KTN3379 potentiates the antitumor effects of a BRaf/MEK inhibitor combination in an A375 mouse xenograft model. Evaluation of mRNA databases of human tumors with 403 melanoma and 2204 CRC tumors revealed a low prevalence of NRG overexpression (1.2% and 0.8%, respectively) in these tumor types where activating BRaf mutations are common. By contrast, thyroid cancer- which has a 60% prevalence of BRaf mutations- expresses high levels of NRG, supporting a potential combination of KTN3379 with a BRaf/MEK pathway inhibitor in this setting. Currently, we are evaluating the combination of KTN3379 with vemurafenib in BRaf-mutated thyroid cancer in a Phase 1 study at Memorial Sloan Kettering Cancer Center. Citation Format: Gwenda F. Ligon, Jay S. Lillquist, Theresa M. LaVallee, Diego Alvarado. KTN3379 overcomes ErbB3-mediated resistance of BRaf/MEK inhibition in BRaf-mutated melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A154.
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