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. Author manuscript; available in PMC: 2022 Dec 6.
Published in final edited form as: Dev Cell. 2021 Oct 20;56(23):3264–3275.e7. doi: 10.1016/j.devcel.2021.09.023

Figure 4: CLIP-170S expression in tumor biopsies is enriched in patients resistant to cabazitaxel therapy and associated with lower progression-free survival; Computational prediction of Imatinib, as a drug that reverses taxane resistance in GC.

Figure 4:

A) Swimmers plot shows the duration of cabazitaxel treatment (months) for each patient. Best response status is annotated based on RECIST 1.1 criteria (stable disease, blue circles; progressive disease, red triangles) with the 3-month cutoff marked with the dotted red line. Bars are color coded based on CLIP-170 isoform expression (blue bars, canonical CLIP-170; salmon bars, CLIP-170S isoform). B) Kaplan-Meier curve of PFS for canonical CLIP-170 (blue) versus CLIP-170S (red) with median PFS: 3.01 months [95% CI:1.15–5.72] and PFS: 1.17 months [95% CI:0.95–1.61], respectively; HR=4.35 (95% CI:1.59–11.91), log-rank p=0.002. Number at risk indicates the number of patients without progression at each time point, according to CLIP-170S status (CLIP-170, blue; CLIP-170S, red). C) Schematic representation of computational approach used to identify drugs predicted to reverse taxane resistance. A DTX-resistance gene signature was identified using RNA-Seq data from untreated and docetaxel-treated sensitive and resistant GC cell lines (Accession number: PRJNA594148). This gene signature was used to query the Connectivity Map (CMAP) database, to identify compounds whose transcriptional output was negatively correlated to the DTX-resistance gene signature. D) Scatter density dot plot of 1309 screened small molecules from the CMAP database whose transcriptional outputs were quantified based on their reversal relationship with the DTX-resistance signature. A lower negative Effect Score indicates higher likelihood to reverse the DTX-resistance. E) Imatinib sensitizes HS746T cells to docetaxel. Cytotoxicity assay using DTX-resistant Hs746T cells treated with docetaxel (DTX) or imatinib (IMA) either alone or in combination (DTX + IMA). F) Imatinib selectively inhibits CLIP-170S expression without affecting CLIP-170. Hs746T and TMK1 cells were treated with 1, 25, 50 and 100 μM Imatinib for 3 hr and processed for immunoblotting using antibodies against the C-terminus of CLIP-170 or tubulin. G) Imatinib has no effect on Hs746T-CLIP-170-KD sensitivity to docetaxel. Cytotoxicity assay as in B.