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by claude@2026-07, 2026-07-04
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The study aimed to find small-molecule vulnerabilities that enhance the efficacy of the proteasome inhibitor carfilzomib (CFZ) in multiple myeloma, including CFZ-resistant cells, using a chemical screen and mechanistic follow-up. The authors found bedaquiline (and its fumarate salt) as a potent synergistic partner: BDQ+CFZ increased cytotoxicity and apoptosis in PI-sensitive and PI-resistant multiple myeloma cells, in AL amyloidosis and other B-cell malignancies, while showing minimal toxicity to normal cells. Mechanistically, BDQ targeted the mitochondrial ATP synthase ATP5F1C subunit, intensified proteotoxic stress, and specifically boosted CFZ’s inhibition of the proteasome chymotrypsin-like activity, selectively interacting with proteasome/ubiquitin-activating enzyme inhibitors. A stated limitation is that the work was focused on in vitro and model-system efficacy and mechanism rather than presenting clinical data. Relevance to endometriosis: the paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via keyword match in the upstream search index.
Abstract
ABSTRACT Proteasome inhibitors (PIs) are cornerstone therapies for multiple myeloma (MM), yet resistance remains a major barrier to durable responses. To identify druggable vulnerabilities that enhance PIs efficacy, we performed a small-molecule chemical screen in the presence of carfilzomib (CFZ). We identified bedaquiline (BDQ), an FDA-approved antimycobacterial agent, as a potent synergistic partner. BDQ and its fumarate salt (BDQ-F) significantly amplified CFZ-induced cytotoxicity in PI-sensitive and PI-resistant MM cells, in AL amyloidosis and other B-cell malignancies, with minimal toxicity toward normal cells. Mechanistic studies confirmed that BDQ specifically targets the ATP5F1C subunit of mitochondrial ATP synthase. BDQ-CFZ combination triggered extensive apoptosis, exacerbating proteotoxic stress and proteasome-associated pathways. BDQ specifically enhanced CFZ’s inhibition of the proteasome’s chymotrypsin-like activity. Importantly, BDQ synergized with multiple proteasome and ubiquitin-activating enzyme inhibitors, but not with other standard MM agents, underscoring its selective interaction with the UPS pathway. BDQ-CFZ co-treatment markedly reduced MM cell viability and tumor burden in patient-derived cells and zebrafish xenograft models. These findings support the therapeutic repurposing of BDQ to potentiate PIs efficacy and overcome resistance in MM and related B-cell malignancies. KEY POINTS Bedaquiline synergizes with proteasome inhibitors in MM and other hematologic malignancies, sparing normal cells Bedaquiline targets ATP synthase γ and boosts carfilzomib by enhancing chymotrypsin-like proteasome inhibition NOVELTY We identify the antimicrobial bedaquiline and its fumarate salt as potent enhancers of proteasome inhibitor efficacy in multiple myeloma and other B-cell malignancies. By inhibiting ATP synthase γ, bedaquiline amplifies chymotrypsin-like proteasome inhibition and overcomes drug resistance. This study reveals a mitochondria– proteasome vulnerability and proposes a clinically actionable strategy to restore sensitivity and reduce toxicity of proteasome-based therapies. VISUAL ABSTRACT
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ABSTRACT
Proteasome inhibitors (PIs) are cornerstone therapies for multiple myeloma (MM), yet resistance remains a major barrier to durable responses. To identify druggable vulnerabilities that enhance PIs efficacy, we performed a small-molecule chemical screen in the presence of carfilzomib (CFZ). We identified bedaquiline (BDQ), an FDA-approved antimycobacterial agent, as a potent synergistic partner. BDQ and its fumarate salt (BDQ-F) significantly amplified CFZ-induced cytotoxicity in PI-sensitive and PI-resistant MM cells, in AL amyloidosis and other B-cell malignancies, with minimal toxicity toward normal cells. Mechanistic studies confirmed that BDQ specifically targets the ATP5F1C subunit of mitochondrial ATP synthase. BDQ-CFZ combination triggered extensive apoptosis, exacerbating proteotoxic stress and proteasome-associated pathways. BDQ specifically enhanced CFZ’s inhibition of the proteasome’s chymotrypsin-like activity. Importantly, BDQ synergized with multiple proteasome and ubiquitin-activating enzyme inhibitors, but not with other standard MM agents, underscoring its selective interaction with the UPS pathway. BDQ-CFZ co-treatment markedly reduced MM cell viability and tumor burden in patient-derived cells and zebrafish xenograft models. These findings support the therapeutic repurposing of BDQ to potentiate PIs efficacy and overcome resistance in MM and related B-cell malignancies.
KEY POINTS
Bedaquiline synergizes with proteasome inhibitors in MM and other hematologic malignancies, sparing normal cells
Bedaquiline targets ATP synthase γ and boosts carfilzomib by enhancing chymotrypsin-like proteasome inhibition
NOVELTY We identify the antimicrobial bedaquiline and its fumarate salt as potent enhancers of proteasome inhibitor efficacy in multiple myeloma and other B-cell malignancies. By inhibiting ATP synthase γ, bedaquiline amplifies chymotrypsin-like proteasome inhibition and overcomes drug resistance. This study reveals a mitochondria– proteasome vulnerability and proposes a clinically actionable strategy to restore sensitivity and reduce toxicity of proteasome-based therapies.
Competing Interest Statement
The authors have declared no competing interest.
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