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Imatinib overrides taxane resistance by selective inhibition of novel CLIP1 variant obstructing the microtubule pore

Katsuhiro Kita, Prashant V. Thakkar, Giuseppe Galletti, Neel Madhukar, Elena Vila Navarro, Isabel Barasoain, Holly V. Goodson, Dan Sackett, José Fernando Díaz, Olivier Elemento, Manish A. Shah, Paraskevi Giannakakou
doi: https://doi.org/10.1101/838334
Katsuhiro Kita
1Weill Cornell Medicine, New York, NY
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Prashant V. Thakkar
1Weill Cornell Medicine, New York, NY
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Giuseppe Galletti
1Weill Cornell Medicine, New York, NY
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Neel Madhukar
1Weill Cornell Medicine, New York, NY
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Elena Vila Navarro
1Weill Cornell Medicine, New York, NY
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Isabel Barasoain
2Centro de Investigaciones Biológicas, Madrid, Spain
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Holly V. Goodson
3University of Notre Dame, IN
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Dan Sackett
4Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD
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José Fernando Díaz
2Centro de Investigaciones Biológicas, Madrid, Spain
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Olivier Elemento
1Weill Cornell Medicine, New York, NY
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  • For correspondence: pag2015@med.cornell.edu mas9313@med.cornell.edu ole2001@med.cornell.edu
Manish A. Shah
1Weill Cornell Medicine, New York, NY
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  • For correspondence: pag2015@med.cornell.edu mas9313@med.cornell.edu ole2001@med.cornell.edu
Paraskevi Giannakakou
1Weill Cornell Medicine, New York, NY
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  • For correspondence: pag2015@med.cornell.edu mas9313@med.cornell.edu ole2001@med.cornell.edu
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Abstract

Despite its widespread use, the majority of patients with gastric cancer (GC) will not respond to taxane chemotherapy due to resistance mechanisms. Here, we report the discovery of a novel truncated variant of the microtubule plus-end binding protein (+TIP) CLIP-170, hereafter CLIP-170S, whose expression is enriched in taxane resistant cell lines and patients with GC. To establish causation, we knocked-down (KD) CLIP-170S which completely reversed taxane resistance. Mass-spec proteomics and 5’-RACE further showed that CLIP-170S lacked the first 150 amino acids, including the Cap-Gly motif required for microtubule (MT) plus-end localization. Mechanistically, we show that CLIP-170S was mislocalized from the MT plus-end to the MT lattice obstructing the MT pore surface site required for taxane entry into the MT lumen. Computational analysis of RNA-seq data from taxane-sensitive and resistant GC cell lines, predicted imatinib as the top candidate drug to overcome drug resistance. Imatinib treatment completely reversed taxane resistance, as predicted, and did so unexpectedly by selective depletion of CLIP-170S. Importantly, CLIP170S was found to be highly prevalent in tumor biopsies from patients with GC. Taken together, these data identify CLIP-170S as a novel, clinically prevalent +TIP variant that obstructs the MT pore and confers taxane resistance. The discovery of this previously unrecognized variant together with the computational discovery of Imatinib as a selective CLIP-170S inhibitor, implicate the MT pore in clinical taxane resistance and provide new therapeutic opportunities for treatment of GC and beyond.

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Posted November 11, 2019.
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Imatinib overrides taxane resistance by selective inhibition of novel CLIP1 variant obstructing the microtubule pore
Katsuhiro Kita, Prashant V. Thakkar, Giuseppe Galletti, Neel Madhukar, Elena Vila Navarro, Isabel Barasoain, Holly V. Goodson, Dan Sackett, José Fernando Díaz, Olivier Elemento, Manish A. Shah, Paraskevi Giannakakou
bioRxiv 838334; doi: https://doi.org/10.1101/838334
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Imatinib overrides taxane resistance by selective inhibition of novel CLIP1 variant obstructing the microtubule pore
Katsuhiro Kita, Prashant V. Thakkar, Giuseppe Galletti, Neel Madhukar, Elena Vila Navarro, Isabel Barasoain, Holly V. Goodson, Dan Sackett, José Fernando Díaz, Olivier Elemento, Manish A. Shah, Paraskevi Giannakakou
bioRxiv 838334; doi: https://doi.org/10.1101/838334

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