This PDF file includes:

• Supplementary Methods
• Fig. S1. GDSC parameters on selected compounds.
• Fig. S2. Resistance potential assay on all parental cell lines used in the study.
• Fig. S3. Characterization of paclitaxel-resistant cancer cells for cell cycle progression and collateral resistance to other microtubule-targeting drugs.
• Fig. S4. Collateral EGFR-TKI resistance in paclitaxel-resistant cancer cells.
• Fig. S5. Collateral gefitinib resistance in paclitaxel-resistant xenograft tumors.
• Fig. S6. GDSC-based coresistance ranking of some microtubule-targeting drugs with EGFR-TKIs and validation study using epothilone B–resistant cell lines.
• Fig. S7. BrdU incorporation assay on all EGFR-TKI persister models used in the study.
• Fig. S8. Characterization of GPs derived from EGFR-TKI hypersensitive cell lines.
• Fig. S9. Characterization of EMT profile.
• Fig. S10. β-Catenin translocation and invadopodia protrusion are correlated with stemness in GPs derived from paclitaxel-resistant cancer cells.
• Fig. S11. Characterization of glycolysis parameters in EGFR-TKI persisters.
• Fig. S12. FOXO3a activation is associated with the metastatic propensity of paclitaxel-resistant tumors.
• Fig. S13. FOXO3a expression is correlated with therapy relapse breast cancer patients and with drug resistance to various chemotherapy and targeted therapy agents in cancer cell lines.
• Fig. S14. Consequences of FOXO3a inhibition in GPs derived from transient and stable paclitaxel-resistant cells.
• Fig. S15. FOXO3a affects protein kinase activities of EGFR and downstream signaling to facilitate apoptosis rewiring in PTXR-derived GPs.
• Fig. S16. Phenotypic consequences of FOXO3a inhibition on the state of apoptosis and stemness.
• Fig. S17. Expression and activity of ABC drug efflux pumps are not required for a more stable secondary EGFR-TKI resistance.
• Fig. S18. MET amplification is dispensable for entering gefitinib persistence in paclitaxel-resistant cancer cells.
• Fig. S19. Mutant KRAS is dispensable for collateral EGFR-TKI persistence development in paclitaxel-resistant cancer cells.
• Fig. S20. Calculated IC₅₀ values.
• Table S1. Clinicopathologic information of human breast cancer patients.
• Table S2. Primer sequences for qRT-PCR.

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