CLIP-170S is a microtubule +TIP variant that confers resistance to taxanes by impairing drug-target engagement.
Dev Cell
; 56(23): 3264-3275.e7, 2021 12 06.
Article
en En
| MEDLINE
| ID: mdl-34672971
ABSTRACT
Taxanes are widely used cancer chemotherapeutics. However, intrinsic resistance limits their efficacy without any actionable resistance mechanism. We have discovered a microtubule (MT) plus-end-binding CLIP-170 protein variant, hereafter CLIP-170S, which we found enriched in taxane-resistant cell lines and patient samples. CLIP-170S lacks the first Cap-Gly motif, forms longer comets, and impairs taxane access to its MT luminal binding site. CLIP-170S knockdown reversed taxane resistance in cells and xenografts, whereas its re-expression led to resistance, suggesting causation. Using a computational approach in conjunction with the connectivity map, we unexpectedly discovered that Imatinib was predicted to reverse CLIP-170S-mediated taxane resistance. Indeed, Imatinib treatment selectively depleted CLIP-170S, thus completely reversing taxane resistance. Other RTK inhibitors also depleted CLIP-170S, suggesting a class effect. Herein, we identify CLIP-170S as a clinically prevalent variant that confers taxane resistance, whereas the discovery of Imatinib as a CLIP-170S inhibitor provides novel therapeutic opportunities for future trials.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Neoplasias Gástricas
/
Eliminación de Gen
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Resistencia a Antineoplásicos
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Taxoides
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Mesilato de Imatinib
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Proteínas Asociadas a Microtúbulos
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Proteínas de Neoplasias
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Recurrencia Local de Neoplasia
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Dev Cell
Asunto de la revista:
EMBRIOLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos