>> Studies from our laboratory and others have shown that acquired lapatinib resistance is, at least in part, ascribed to activation of compensatory kinase pathways, including upregulation of ERBB family proteins and subsequent reactivation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling (Garrett et al., 2011, Canfield et al., 2015) <<
sciencedirect.com
and this just out, unrelated to the CDX-3379 business plan......
Cold Spring Harb Mol Case Stud. 2019 Dec 13;5(6). pii: a004341. doi: 10.1101/mcs.a004341. Print 2019 Dec.
Heterogeneous alteration of the ERBB3-MYC axis associated with MEK inhibitor resistance in a KRAS-mutated low-grade serous ovarian cancer patient.
Colombo I#1, Garg S#1, Danesh A2, Bruce J2, Shaw P3, Tan Q1, Quevedo R2, Braunstein M1, Oza AM1, Pugh T2,4, Lheureux S1.
1
Bras Family Drug Development Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario M5G 1Z5, Canada.
2
Princess Margaret Genomics Centre, University Health Network, Toronto, Ontario M5G 1Z5, Canada.
3
Affiliate Scientist, University Health Network, Toronto, Ontario M5G 1Z5, Canada.
4
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1Z5, Canada.
#
Contributed equally
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 KRAS-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 ERBB3 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 KRAS-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. |
