AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer

Divine, Laura M.; Nguyen, Mai; Meller, E.H.; Desai, Riva A; Arif, Batool; Rankin, Erinn B.; Bligard, Katherine H.; Meyerson, Cherise; Hagemann, Ian S.; Massad, M.N.; Thaker, Premal H.; Hagemann, Andrea R.; McCourt, Carolyn K.; Powell, M.A.; Mutch, David G.; Fuh, Katherine C.

doi:10.18632/oncotarget.12637

Cited by 28 publications

(31 citation statements)

References 62 publications

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“…5). In agreement with previous findings in our laboratory, AXL inhibition alone was not found to significantly decrease proliferation in xenograft models [6]. These results indicate that AXL inhibition enhances USC sensitivity to paclitaxel in vivo .…”

Section: Resultssupporting

confidence: 93%

“…Finally, we report that inhibition of AXL with BGB324 acts in an additive fashion with paclitaxel to reduce tumor burden in an in vivo xenograft model of USC. Combined with our previous observations that AXL was required for uterine cancer cell invasion and metastasis, and that AXL expression correlated with overall worse prognosis in uterine cancer patients [6], these findings provide strong preclinical support for combining an AXL inhibitor with paclitaxel in USC clinical trials.…”

Section: Discussionsupporting

confidence: 73%

“…Additionally, we found that AXL was required for migration and invasion of the USC cell line ARK1 in vitro and that ARK1 cells in which AXL was knocked down produced smaller tumor burden than AXL-expressing cells in a metastatic xenograft model [6]. These data were consistent with findings that AXL is a critical player in the metastatic potential and overall prognosis of numerous other solid cancers [7-11].…”

Section: Introductionsupporting

confidence: 86%

“…Although this drug has not been used extensively in gynecologic cancers, preclinical data show success with BGB324 as monotherapy and in combination treatment in cancers such as acute myeloid leukemia (AML), non-small cell lung cancer (NSCLC), melanoma, breast, head and neck, esophageal, prostate, and endometrial [6, 16, 17, 25, 54-57]. Synergism between BGB324 and taxane therapy has been demonstrated in other tumor types [16, 25], and BGB324 is currently being investigated in several phase I/II trials.…”

Section: Discussionmentioning

confidence: 99%

“…Given these findings that AXL promotes chemoresistance in other cancers and our findings that AXL is required for uterine cancer cell migration, invasion, and metastasis [6], our objective here was to assess the role of AXL in chemoresistance in USC. We report that AXL expression mediates USC resistance to paclitaxel-induced cell cycle arrest and apoptosis independently of EMT.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

Palisoul

Quinn

Schepers

et al. 2017

Molecular Cancer Therapeutics

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Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo. We used small hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial-mesenchymal transition in AXL-mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the epithelial-mesenchymal transition in vitro. Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared to no treatment or single agent treatments (P<0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 73%