Altered ribosomal profile in acquired resistance and reversal associates with pathological response to chemotherapy in inflammatory breast cancer.

ABSTRACT

Therapeutic resistance presents a significant hurdle in combating inflammatory breast cancer (IBC), adding to the complexity of its management. To investigate these mechanisms, we conducted a comprehensive analysis using transcriptomic and proteomic profiling in a preclinical model alone with correlates of treatment response in IBC patients. This included SUM149 cell lines derived from treatment-naïve patients, along with acquired drug resistance (rSUM149) and others in a state of resistance reversal (rrSUM149), aiming to uncover drug resistance networks. We identified specific ribosomal proteins associated with acquiring resistance. These correlated with elevated levels of molecular markers such as pERK, CDK1, XIAP, and SOD2. While resistance reversal in rrSUM149 cells largely normalized the expression profile, VIPER analysis revealed persistent alterations in ribosomal process-related proteins (AGO2, Exportin 1, RPL5), suggesting their continued involvement in drug resistance. Moreover, genes linked to ribosomal processes were significantly enriched (P < 0.001) among overexpressed genes in IBC patients (n = 87) who exhibited a pathological complete response (pCR) to neoadjuvant chemotherapy. Given the common hyperactivation of MAPK in IBC tumors, including rSUM149, we evaluated Merestinib, a multikinase inhibitor in clinical trials. It effectively targeted pERK and peIF4E pathways, suppressed downstream targets, induced cell death in drug-resistant rSUM149 cells, and showed synergistic effects with another tyrosine kinase inhibitor (Lapatinib) in parental cells. This underscores its significant impact on protein synthesis signaling, crucial for combating translational dependence in cancer cells. In summary, our study elucidates adaptive changes in IBC cells in response to therapy and treatment pauses, guiding precision medicine approaches for this challenging cancer type.