Justin Taylor: Happy to Share Our Latest Paper on XPO1 R749Q Mutations Online Ahead of Print in Cancer Research
Justin Taylor, Assistant Professor at the UM Sylvester Comprehensive Cancer Center, shared on X:
“Happy to share our latest paper online ahead of print in Cancer Research
XPO1 R749Q Mutations Co-occur with POLE Mutations in Cancer and can be Targeted to Overcome Chemoresistance
Great collaboration with Caris Life Sciences and Hai Dang Nguyen!
Thanks to these collaborations, we were able to conduct analysis of 217,570 pan-cancer tumor sequencing data to identify XPO1 mutations. We previously reported on XPO1 E571K in hematologic malignancies
Now we discovered that XPO1 R749Q mutations are enriched in endometrial and colon cancer! These co-occurred highly with POLE mutations. In our CRISPR knock-in lines of this mutation, we discovered that the mutation leads to chemoresistance to topoisomerase I inhibition.
With help from Ryan Notti to help us understand how XPO1 R749Q could structurally impact the function of XPO1 to export its nuclear cargoes. Simulations show that R749Q could cause a charge cluster switch that affects the distal portion of the H9 regulatory loop.
These changes in XPO1 regulation lead to increased nuclear export including many DNA repair proteins and functionally resistance to the topoisomerase I class of chemotherapies specifically. We figured out the mechanism and overcome the resistance by blocking XPO1 with selinexor.
The combination of selinexor and irinotecan could have impact even outside of this specific XPO1 mutation and should be further explored in colon cancer based on our preclinical data. Endometrial cancer is another potential area for exploration!”
Title: XPO1R749Q Mutations Co-occur with POLE Mutations in Cancer and can be Targeted to Overcome Chemoresistance
Authors: Tulasigeri M. Totiger, Wannasiri Chiraphapphaiboon, Yasmine Baca, Sana Chaudhry, Ryan Q. Notti, Skye Montoya, Monika Chojnacka, Gabriel Gaidosh, Jumana Afaghani, Maurizio Affer, Christopher Armstrong, Paul M. Kavanaugh, Efe Karaca, Jenna Zabroski, Michael Lewis, Alyssa Maye, Jacob Jahn, Rajesh K. Soni, Daniel Bilbao, Phil Walker, Andrew Elliott, Emil Lou, Wafik S. El-Deiry, Jose Antonio Rodriguez, Hai Dang Nguyen, Justin Taylor
Title: Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis
Authors: Justin Taylor, Maria Sendino, Alexander N. Gorelick, Alessandro Pastore, Matthew T. Chang, Alexander V. Penson, Elena I. Gavrila, Connor Stewart, Ella M. Melnik, Florisela Herrejon Chavez, Lillian Bitner, Akihide Yoshimi, Stanley Chun-Wei Lee, Daichi Inoue, Bo Liu, Xiao J. Zhang, Anthony R. Mato, Ahmet Dogan, Michael G. Kharas, Yuhong Chen, Demin Wang, Rajesh K. Soni, Ronald C. Hendrickson, Gorka Prieto, Jose A. Rodriguez, Barry S. Taylor, Omar Abdel-Wahab
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