The cytotoxic activity of carfilzomib together with nelfinavir is superior to the bortezomib/nelfinavir combination in non-small cell lung carcinoma

Chemotherapy resistance is still a major problem in the treatment of patients with non-small-cell-lung carcinoma (NSCLC), and novel concepts for the induction of cytotoxicity in NSCLC are highly warranted. Proteotoxicity, the induction of cytotoxicity by targeting the ubiquitin proteasome system, represents an appealing innovative strategy. The combination of the proteasome inhibitor bortezomib (BTZ) and the proteotoxic stress-inducing HIV drug nelfinavir (NFV) synergistically induces proteotoxicity and shows encouraging preclinical efficacy in NSCLC. The second-generation proteasome inhibitor carfilzomib (CFZ) is superior to BTZ and overcomes BTZ resistance in multiple myeloma patients. Here, we show that CFZ together with NFV is superior to the BTZ + NFV combination in inducing endoplasmic reticulum stress and proteotoxicity through the accumulation of excess proteasomal substrate protein in NSCLC in vitro and ex vivo. Interestingly, NFV increases the intracellular availability of CFZ through inhibition of CFZ export from NSCLC cells that express multidrug resistance (MDR) protein. Combining CFZ with NFV may therefore represent a future treatment option for NSCLC, which warrants further investigation.

 

Comments：

The statement highlights the challenges in treating non-small-cell-lung carcinoma (NSCLC) due to chemotherapy resistance and the need for novel strategies to induce cytotoxicity. One such strategy is proteotoxicity, which involves targeting the ubiquitin proteasome system. The combination of the proteasome inhibitor bortezomib (BTZ) and the HIV drug nelfinavir (NFV) has shown promising results in inducing proteotoxicity in NSCLC. However, the second-generation proteasome inhibitor carfilzomib (CFZ) has been found to be superior to BTZ and can overcome BTZ resistance in multiple myeloma patients.

The statement further reports that CFZ, when combined with NFV, is more effective than the BTZ + NFV combination in inducing endoplasmic reticulum stress and proteotoxicity in NSCLC in vitro and ex vivo. Moreover, the statement suggests that NFV can increase the intracellular availability of CFZ by inhibiting its export from NSCLC cells expressing multidrug resistance (MDR) protein. Thus, combining CFZ with NFV may represent a promising future treatment option for NSCLC, which requires further investigation.

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