Understanding the XPO7:SLK complex to formulate synergistic combination therapies

Most translational efforts for uncommon cancers stem from oncogenic mutations identified by sequencing. In contrast to genomic analyses, the tumor proteome has the potential to better approximate phenotype-inducing alterations, particularly in the absence of targetable driver mutations. However, tumor analyses using mass spectrometry can be challenging. Exosomes (small extracellular membrane-enclosed vesicles) may circumvent these issues and serve as a valuable, prioritized, “window” into the tumor cell proteome. Applying this reasoning to bile duct cancers (cholangiocarcinoma, CCA), we performed mass spectrometry on exosomes extracted from patient bile, revealing a 17-fold enhancement of the nuclear export protein XPO7. Immunohistochemistry analysis of XPO7 expression in 318 CCA patients unexpectedly demonstrated intense cytoplasmic staining. Within the cytosol we demonstrate that XPO7 exists in a molecular complex with the serine/threonine kinase SLK. shRNA-mediated knockdown of either XPO7 or SLK in CCA lines abrogated tumor organoid formation and reduced orthotopic tumor growth. To translate the target to patients, we identified tivozanib as a potent SLK inhibitor. Tivozanib treatment reduced tumor organoid formation in vitro and induced tumor regression in vivo in patient derived xenografts (n=2). Together, these findings reveal a novel cytosolic XPO7:SLK signaling axis that is targetable in CCA patients and we have already documented early responses with our accruing Phase I/II trial (NCT 04645160). It is however clear that single agents will not result in cures for patients with solid tumors, and a better understanding of the XPO7:SLK complex (including downstream oncogenic signaling axes) will be required to formulate and implement synergistic combination therapies.