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Sensitivity to splicing modulation of BCL2 family genes defines cancer therapeutic strategies for splicing modulators.
Aird, Daniel; Teng, Teng; Huang, Chia-Ling; Pazolli, Ermira; Banka, Deepti; Cheung-Ong, Kahlin; Eifert, Cheryl; Furman, Craig; Wu, Zhenhua Jeremy; Seiler, Michael; Buonamici, Silvia; Fekkes, Peter; Karr, Craig; Palacino, James; Park, Eunice; Smith, Peter G; Yu, Lihua; Mizui, Yoshiharu; Warmuth, Markus; Chicas, Agustin; Corson, Laura; Zhu, Ping.
Affiliation
  • Aird D; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Teng T; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Huang CL; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Pazolli E; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Banka D; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Cheung-Ong K; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Eifert C; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Furman C; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Wu ZJ; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Seiler M; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Buonamici S; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Fekkes P; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Karr C; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Palacino J; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Park E; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Smith PG; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Yu L; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Mizui Y; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Warmuth M; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Chicas A; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Corson L; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
  • Zhu P; H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA, 02139, USA. ping_zhu@h3biomedicine.com.
Nat Commun ; 10(1): 137, 2019 01 11.
Article in En | MEDLINE | ID: mdl-30635584
Dysregulation of RNA splicing by spliceosome mutations or in cancer genes is increasingly recognized as a hallmark of cancer. Small molecule splicing modulators have been introduced into clinical trials to treat solid tumors or leukemia bearing recurrent spliceosome mutations. Nevertheless, further investigation of the molecular mechanisms that may enlighten therapeutic strategies for splicing modulators is highly desired. Here, using unbiased functional approaches, we report that the sensitivity to splicing modulation of the anti-apoptotic BCL2 family genes is a key mechanism underlying preferential cytotoxicity induced by the SF3b-targeting splicing modulator E7107. While BCL2A1, BCL2L2 and MCL1 are prone to splicing perturbation, BCL2L1 exhibits resistance to E7107-induced splicing modulation. Consequently, E7107 selectively induces apoptosis in BCL2A1-dependent melanoma cells and MCL1-dependent NSCLC cells. Furthermore, combination of BCLxL (BCL2L1-encoded) inhibitors and E7107 remarkably enhances cytotoxicity in cancer cells. These findings inform mechanism-based approaches to the future clinical development of splicing modulators in cancer treatment.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Minor Histocompatibility Antigens / RNA Splicing / Carcinoma, Non-Small-Cell Lung / Proto-Oncogene Proteins c-bcl-2 / Apoptosis Regulatory Proteins / Bcl-X Protein / Myeloid Cell Leukemia Sequence 1 Protein / Lung Neoplasms / Melanoma Type of study: Diagnostic_studies / Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2019 Document type: Article Affiliation country: Estados Unidos Country of publication: Reino Unido
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Minor Histocompatibility Antigens / RNA Splicing / Carcinoma, Non-Small-Cell Lung / Proto-Oncogene Proteins c-bcl-2 / Apoptosis Regulatory Proteins / Bcl-X Protein / Myeloid Cell Leukemia Sequence 1 Protein / Lung Neoplasms / Melanoma Type of study: Diagnostic_studies / Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2019 Document type: Article Affiliation country: Estados Unidos Country of publication: Reino Unido