RESUMO
SMARCA2 and SMARCA4 are the mutually exclusive catalytic subunits of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, and have recently been considered as attractive synthetic lethal targets for PROTAC-based cancer therapy. However, the potential off-tissue toxicity towards normal tissues remains a concern. Here, we optimize a GSH-inducible SMARCA2/4-based PROTAC precursor with selective antitumor activity towards lung cancer cells and negligible cytotoxicity towards normal cells in both in vitro and in vivo studies. The precursor is not bioactive or cytotoxic, but preferentially responds to endogenous GSH in GSH-rich lung cancer cells, releasing active PROTAC to degrade SMARCA2/4 via PROTAC-mediated proteasome pathway. Subsequent xenograft model study reveals that selective SMARCA2/4 degradation in lung tumors triggers DNA damage and apoptosis, which significantly inhibits lung cancer cell proliferation without obvious adverse events towards normal tissues. This study exemplifies the targeted degradation of SMARCA2/4 in lung cancer cells by the GSH-responsive PROTAC precursor, highlighting its potential as an encouraging cancer therapeutic strategy.
RESUMO
The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.
Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Fatores de Transcrição , Humanos , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Fator 2 de Transcrição de OctâmeroRESUMO
The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.