Ceritinib overcomes proteasome inhibitor resistance in multiple myeloma by suppressing the protein folding response.

Proteasome inhibitor (PI) resistance remains a major therapeutic obstacle in the treatment of multiple myeloma (MM). MM cells demonstrate pronounced dependence on insulin and insulin-like growth factor-1 signaling via their cognate receptors, IGF-1R and INSR. In this study, we identify ceritinib, a clinically approved inhibitor of anaplastic lymphoma kinase (ALK), as a drug, which can inhibit IGF-1R/INSR activity and downstream PI3K/AKT/mTORC1 signaling. Ceritinib can overcome PI-resistance in MM when used in combination with carfilzomib. This synergy was consistently observed across in vitro and in vivo models, and primary patient-derived MM cells. Mechanistically, MM cells exploit IGF- 1R/INSR signaling to sustain expression of key molecular chaperones, including HSP70 and BiP, which are critical for maintaining proteostasis under conditions of high protein synthesis and turnover. Pharmacological inhibition of IGF-1R/INSR signaling by ceritinib abrogates this adaptive stress response, thereby preventing the upregulation of cytoprotective heat shock proteins upon proteasome inhibition. This disruption results in enhanced accumulation of protein aggregates, increased protein polyubiquitination, endoplasmic reticulum stress, and activation of apoptotic pathways. Collectively, our findings support the repurposing of ceritinib in combination with carfilzomib as a translationally relevant and safe strategy to circumvent PI resistance in MM, warranting further clinical investigation in the relapsed/refractory disease setting.