The emergence of cross‑resistance between anticancer agents poses a major challenge to effective sequential therapy. To determine whether resistance to one chemotherapeutic agent confers resistance to another, we examined cisplatin‑ and doxorubicin‑resistant HeLa and HepG2 models generated through iterative pulse‑selection, a process known to induce stable resistance phenotypes while preserving lineage‑specific characteristics. Drug sensitivity profiling using MTT assays showed that each resistant line exhibited elevated IC₅₀ values and reduced apoptosis exclusively toward its selecting drug, consistent with drug‑specific apoptosis evasion. However, both cisplatin‑ and doxorubicin‑resistant cells retained full sensitivity to the alternate agent, with survival curves and apoptotic responses comparable to parental controls, indicating the absence of generalized cross‑resistance. Transcriptomic analysis further revealed that the two resistance states were governed by largely non‑overlapping molecular programs. Only a small subset of differentially expressed genes was shared, whereas pathway enrichment highlighted Rap1 signaling and drug‑metabolism enzymes in doxorubicin resistance, and PI3K signaling together with H3K27 demethylase‑associated genes in cisplatin resistance. These findings demonstrate that cisplatin and doxorubicin resistance arise through distinct adaptive mechanisms and support the concept that these agents remain mutually effective even in resistant cellular contexts.
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