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. Author manuscript; available in PMC: 2026 Jun 19.
Published in final edited form as: Cell Rep. 2018 Dec 26;25(13):3706–3720.e8. doi: 10.1016/j.celrep.2018.12.017

Figure 5. Identification of an ATIS following Resistance.

Figure 5.

(A) Schematic for identification of reversible and irreversible gene changes after VEGFR TKI resistance/withdrawal (left) with a representative volcano plot showing gene expression changes that reverse after ST (green) and LT (blue) withdrawal (right; n = 3; 3T3 SuR cells shown as example; irreversible gene expression changes shown in red).

(B) Heatmaps showing reversible/irreversible gene expression changes after therapy withdrawal (n = 3; 3T3 cell variants shown as example).

(C) Number of upregulated genes (based on GO database for extracellular region term; GO:0005576) in SuR cell variants compared to parental (n = 3; LM2–4, 3T3, and RENCA cell variants shown).

(D) SuR cell variants (n = 3) were compared to known inflammatory pathways and published secretomes induced by oncogenes, cancer therapy, and senescence using GSEA. Note: gene set information is summarized in Data S2.

(E) Identification of 33 ATIS gene members in SuR cell variants (left); GO analysis of ATIS signature for significantly enriched biological process terms (right).

(F and G) GSEA analysis of the ATIS signature in published datasets involving Su treatment in preclinical and clinical studies. (F) Preclinical: enrichment of ATIS in tumor and host tissues derived from a Su-resistant RCC PDX model (n = 4; GEO:GSE76068). Tumor samples obtained pre-treatment (pre-Tx), were compared to samples from sensitive and resistant time points. (G) Clinical: enrichment of ATIS in locally advanced human BC patients responsive or non-responsive to su-treatment, compared to pre-treatment levels (n = 5–7; GEO:GSE58837).

(H) Protein quantification by ELISA in lysates of LM2–4 SuR cell variants for IL-6, IL-1α, and IL-1β (n = 4).

P, parental; SuR, sunitinib-resistant; ST-W, short-term withdrawal; LT-W, long-term withdrawal; NT, not tested; GO, Gene Ontology; GSEA, gene set enrichment analysis; Su, sunitinib; RCC, renal cell carcinoma; BC, breast cancer; PDX, patient-derived xenograft; see STAR Methods for details on use of published data obtained from GEO database. ST-W equaled 2 days; P cells treated with Su (5 μM) for 2 days. Quantitative data are shown as mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001, compared to parental cell lines, unless otherwise noted. See also Figure S4.