Heterogeneous alteration of the ERBB3-MYC axis associated with MEK inhibitor resistance in a -mutated low-grade serous ovarian cancer patient.

Low-grade serous ovarian cancer (LGSOC) is relatively chemoresistant, and no precision therapy is approved for this indication. Despite promising results in phase II trials, MEK inhibitors have failed to show improved progression-free survival in a phase III trial when compared to physician's choice chemotherapy. We report for the first time temporal changes in the tumor genome assessed in sequential tumor samples of a 48-yr-old patient with a -mutated LGSOC treated with the MEK inhibitor binimetinib. After an initial long-lasting partial response, rapidly progressive brain metastasis occurred, ultimately leading to patient death. Our study demonstrates that novel genomic alterations accumulated during the course of treatment as a result of therapeutic pressures led to MEK inhibitor resistance and, ultimately, disease evolution with an aggressive behavior observed in this patient. In particular, we describe the presence of amplification and aberrant ERBB3-MYC signaling as a potential mechanism of acquired MEK inhibitor resistance in a patient with LGSOC, which is similar to previous observations in -mutated colon and lung cancers. Our study highlights the need for an individualized approach to better understand tumor genome evolution and suggests that LGSOC patients may derive improved therapeutic benefit by using a combinatorial strategy used in other cancers in order to overcome emergent resistance to targeted therapies.