# A novel, short isoform of the +TIP microtubule (MT) binding protein CLIP170 confers taxane resistance by obstructing the MT pore

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $61,478

## Abstract

The overarching goal of the parent grant is to elucidate the mechanism of taxane resistance mediated by a novel
variant of the microtubule (MT) plus-end binding protein CLIP-170. The previously unrecognized variant, namely
CLIP-170S, displays unique features and biological properties as compared to the parent protein. We identified
that CLIP-170S confers taxane resistance by obstructing the MT-pore on the MT polymer surface, which then
inhibits taxane access to its high-affinity luminal binding site. Using a computational, systems-biology approach
we further identified the receptor tyrosine kinase (RTK) inhibitor, Imatinib, as a drug predicted to reverse taxaneresistance
in gastric cancer. Experimental validation showed that Imatinib in combination with docetaxel,
reverses entirely taxane resistance by selective depletion of CLIP-170S. Additional RTK inhibitors, such as
ponatinib, sunitinib and axotinib, also downregulate CLIP-170S protein, suggesting a broader class-effect.
However, the mechanism by which Imatinib and other RTK inhibitors downregulate CLIP-170S protein
expression is not known. In this proposal Eiman will investigate a related but novel angle regarding the
modulation of CLIP-170S by Imatinib and other RTK inhibitors, via autophagy. The objective of the current
proposal is to elucidate the role of autophagy in drug-induced CLIP-170S depletion.
Autophagy is a homeostatic, catabolic degradation process whereby cellular proteins and organelles are
engulfed by autophagosomes, digested in lysosomes, and recycled to sustain cellular metabolism (1). Autophagy
on one hand acts as a tumor suppressor by preventing the accumulation of damaged proteins and organelles,
and on the other hand, as a mechanism of tumor cell survival (2). The cell survival autophagy mechanism is
frequently implicated in tumor progression (3), especially in gastric cancer which is the disease focus of the
parent grant, where autophagy has been reported to promote disease progression from localized to metastatic
gastric cancer (4).
Using gastric cancer cell lines expressing CLIP-170S, we found that imatinib selectively depletes this variant
sensitizing cells to taxane chemotherapy. Imatinib is FDA approved for the treatment of chronic myelogenous
leukemia (CML) driven by the Bcr-Abl fusion protein. To the best of our knowledge, there are no reports
implicating Imatinib mechanism of action in the regulation of the MT cytoskeleton which is the target of taxane
chemotherapy. Therefore, there is no known mechanistic link between taxane resistance and Imatinib
mechanism of action. In the parental grant we proposed signaling and computational studies to identify this link,
while the current supplement focuses on the role of autophagy, which is a new line of investigation expected to
contribute and expand the parent grant.
The current proposal is inspired by a recent report showing that Imatinib treatment downregulates Bcr-Abl protein
in CML due to sequestration of Bcr-Abl ...

## Key facts

- **NIH application ID:** 10142706
- **Project number:** 3R01CA228512-03S1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Olivier Elemento
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $61,478
- **Award type:** 3
- **Project period:** 2020-09-01 → 2020-10-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142706

## Citation

> US National Institutes of Health, RePORTER application 10142706, A novel, short isoform of the +TIP microtubule (MT) binding protein CLIP170 confers taxane resistance by obstructing the MT pore (3R01CA228512-03S1). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10142706. Licensed CC0.

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