Targeted Axl inhibition primes chronic lymphocytic leukemia B cells to apoptosis and shows synergistic/additive effects in combination with BTK inhibitors

Sutapa Sinha, Justin Boysen, Michael Nelson, Charla Secreto, Steven L. Warner, David J. Bearss, Connie Lesnick, Tait D. Shanafelt, Neil E. Kay, Asish K. Ghosh

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Purpose: B-cell chronic lymphocytic leukemia (CLL) is an incurable disease despite aggressive therapeutic approaches. We previously found that Axl receptor tyrosine kinase (RTK) plays a critical role in CLL B-cell survival. Here, we explored the possibility of using a high-affinity Axl inhibitor as a single agent or in combination with Bruton's tyrosine kinase (BTK) inhibitors for future clinical trial to treat patients with CLL. Experimental Design: Expression/activation status of other members of the TAM (e.g., Tyro3, Axl, and MER) family of RTKs in CLL B cells was evaluated. Cells were treated with a high-affinity orally bioavailable Axl inhibitor TP-0903 with or without the presence of CLL bone marrow stromal cells (BMSCs). Inhibitory effects of TP-0903 on the Axl signaling pathway were also evaluated in CLL B cells. Finally, cells were exposed to TP-0903 in combination with BTK inhibitors to determine any synergistic/additive effects of the combination. Results: CLL B cells overexpress Tyro3, but not MER. Of interest, Tyro3 remains as constitutively phosphorylated and forms a complex with Axl in CLL B cells. TP-0903 induces massive apoptosis in CLL B cells with LD50 values of nanomolar ranges. Importantly, CLL BMSCs could not protect the leukemic B cells from TP-0903-induced apoptosis. A marked reduction of the antiapoptotic proteins Mcl-1, Bcl-2, and XIAP and upregulation of the proapoptotic protein BIM in CLL B cells was detected as a result of Axl inhibition. Finally, combination of TP-0903 with BTK inhibitors augments CLL B-cell apoptosis. Conclusions: Administration of TP-0903 either as a single agent or in combination with BTK inhibitors may be effective in treating patients with CLL.

Original languageEnglish (US)
Pages (from-to)2115-2126
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number9
DOIs
StatePublished - May 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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