Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

Abstract

Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I-mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K-AKT-mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYCdriven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma-bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. SIGNIFICANCE:Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma-bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1);[59][60][61][62][63][64][65][66][67][68][69][70]

Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors

“…28. Our results showing many primitive functions up-regulated together in tumors raise the possibility of going a step beyond, to simultaneously target multiple independent unicellular processes.…”

Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer

“…We interrogated the therapeutic potential of targeting this axis in SCLC by inhibiting RNA Pol I using the small molecule CX-5461. CX-5461 has been reported to exhibit efficacy in hematopoietic malignancies involving MYC (Devlin et al 2016), and CX-5461 is being tested in clinical trials for leukemia and lymphoma. The efficacy of CX-5461 in autochthonous solid tumors models, however, has not been yet reported.…”

“…Previous studies have focused on the ability of CX-5461 to induce nucleolar stress and p53 activation in mediating in vivo efficacy (Bywater et al 2012;Devlin et al 2016). However, we found significant efficacy in p53-null SCLC, ruling out p53 activation as a relevant factor in the SCLC model.…”

Molecular Regulation of Exercise-Induced Muscle Fiber Hypertrophy

“…The concept of a ceiling on the nuclear DNA/cytoplasm volume relationship is not unique to skeletal muscle and is actually a primary driver of cell division in mitotically active mononucleated cells. In fact, some current strategies in cancer-targeting therapeutics are focused on disrupting the protein synthetic machinery in cancer cells to limit cellular hypertrophy, thereby mitigating proliferation (Devlin et al 2016; Rebello et al 2016). …”