invention diagnoses kinase inhibitor resistant cancer and also decreases
resistance to kinase inhibitors for improved cancer treatments.
cancer therapeutics eventually fail due to cancer’s ability to become resistant
to drugs. How carcinogenic cells achieve this resistance is poorly understood,
with genetic and gene expression changes accounting
for only a small percentage of their adaptability. This invention is a method
to reduce cancer’s resistance to anti-cancer therapeutics, and may be used for triple-negative
breast cancer (TNBC), melanoma, ovarian cancer, and other indications where
MAPK pathway activation is prominent. The invention may also be used to aid in
selecting patients for targeted combination therapies and in monitoring
patients for treatment response and mechanisms of drug resistance.
This technology is based on the discovery that decreased proteolytic shedding of surface receptors, which provide negative feedback on signaling network activity thereby driving post-translational “bypass” signaling pathways, can be caused by anti-cancer kinase inhibitor treatments leading to resistance to those very same therapeutics. Inhibition of multiple signaling pathways, in particular MAPK signaling through MEK1/2, drives “bypass” signaling by causing diminished A Disintegrin and Metalloproteinase (ADAM)-mediated receptor tyrosine kinase (RTK) shedding including MET, HER2, HER4, and especially AXL RTKs. Targeted MEK inhibition (MEKi) has been identified as a promising therapeutic strategy since RAF/MEK /ERK mitogenic phospho-signaling is up-regulated in many cancers including TNBC. MEK, BRAF, p38, JNK and PI3K kinase inhibition have been shown to reduce RTK shedding and hence gives rise to the bypass signaling. This technology increases sensitivity of cancers under treatment with kinase inhibitors by blocking the bypass signaling pathways of RTKs and/or by encouraging RTK receptor shedding.
be used in conjunction with kinase inhibitor cancer treatments to decrease
be used to identify patients likely to respond to kinase inhibitor treatments
and combinations thereof