Sensitivity to splicing modulation of BCL2 family genes defines cancer therapeutic strategies for splicing modulators

Nat Commun. 2019 Jan 11;10(1):137. doi: 10.1038/s41467-018-08150-5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / genetics*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Cell Line, Tumor
  • Doxycycline / pharmacology
  • Drug Synergism
  • Epoxy Compounds / pharmacology
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Macrolides / pharmacology
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Mice
  • Mice, Nude
  • Minor Histocompatibility Antigens / genetics*
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • RNA Interference
  • RNA Splicing / drug effects*
  • RNA Splicing / genetics
  • RNA, Small Interfering / genetics
  • Spliceosomes / drug effects
  • Spliceosomes / genetics
  • Whole Exome Sequencing
  • Xenograft Model Antitumor Assays
  • bcl-X Protein / genetics*

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2-related protein A1
  • BCL2L1 protein, human
  • BCL2L2 protein, human
  • E 7107
  • Epoxy Compounds
  • MCL1 protein, human
  • Macrolides
  • Minor Histocompatibility Antigens
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • bcl-X Protein
  • Doxycycline