Skip to Content
Merck
  • AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs.

AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs.

Cancer research (2014-08-16)
Catherine Wilson, Xiaofen Ye, Thinh Pham, Eva Lin, Sara Chan, Erin McNamara, Richard M Neve, Lisa Belmont, Hartmut Koeppen, Robert L Yauch, Avi Ashkenazi, Jeff Settleman
ABSTRACT

Molecularly targeted drug therapies have revolutionized cancer treatment; however, resistance remains a major limitation to their overall efficacy. Epithelial-to-mesenchymal transition (EMT) has been linked to acquired resistance to tyrosine kinase inhibitors (TKI), independent of mutational resistance mechanisms. AXL is a receptor tyrosine kinase associated with EMT that has been implicated in drug resistance and has emerged as a candidate therapeutic target. Across 643 human cancer cell lines that were analyzed, elevated AXL was strongly associated with a mesenchymal phenotype, particularly in triple-negative breast cancer and non-small cell lung cancer. In an unbiased screen of small-molecule inhibitors of cancer-relevant processes, we discovered that AXL inhibition was specifically synergistic with antimitotic agents in killing cancer cells that had undergone EMT and demonstrated associated TKI resistance. However, we did not find that AXL inhibition alone could overcome acquired resistance to EGFR TKIs in the EMT setting, as previously reported. These findings reveal a novel cotreatment strategy for tumors displaying mesenchymal features that otherwise render them treatment refractory.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Docetaxel, purum, ≥97.0% (HPLC)
Sigma-Aldrich
MISSION® esiRNA, targeting human AXL
USP
Docetaxel, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
MISSION® esiRNA, targeting mouse Axl