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Page 24 of 38 J Cancer Metastasis Treat 2020;6:5 I http://dx.doi.org/10.20517/2394-4722.2020.13

Background and aim: Multiple Myeloma (MM) is a clonal proliferation of neoplastic plasma cells in the
bone marrow. Despite recent therapeutic advances, drug resistance and MM progression is common.
Mouse plasma cell tumors model these antibody producing neoplasms. Long-term genetic studies
utilizing backcross, and congenic strain analyses coupled with positional cloning strategies and functional
studies identified Cdkn2a, Mtor, and Mndal as plasmacytoma susceptibility genes. Tumor incidence
data in congenic strains carrying resistance alleles of Cdkn2a and Mtor led us to hypothesize that drug
combinations affecting these pathways are likely to have an additive, if not synergistic, effect in inhibiting
tumor cell growth.

Experimental procedure: Drug combination [mTOR and histone deacetylases (HDAC) inhibitors] activity
and synergy were measured in B cell neoplasms and NCI-60 cell lines. in vivo activity was assessed in
xenograft experiments. Co-expression network analyses of microarray data from in vitro drug treatment
delineated the cooperative mTORi/HDACi transcriptional response. Selectivity of the response for
genes differentially regulated in MM was determined by GSEA of datasets from healthy controls and
MM patients. The combination’s potential clinical utility was evaluated by developing a multivariate
survival prediction model from the response signature in a MM patient dataset. Functional enrichment
and transcription factor activity testing of the response signature delineated the combination’s biological
activities.

Results: The combination was active and synergistic in 90% of cell lines and controlled in vivo tumor
growth for 12 weeks. Combination response signature genes were correlated with improved survival and
the signature was functionally enriched for cell cycle, apoptosis, antigen presentation, and DNA damage
response. The combination is predicted to repress oncogenic factors and activate tumor suppressors (RB1
and CDKN2A).

Conclusion: The traditional and novel systems-level genomic approaches used to assess combination
activity, disease specificity, and clinical potential demonstrate the efficacy of combined mTORi/HDACi,
and warrant further investigation in clinical trials.

34. tRNA-derived fragment AS-tDR-007333 promotes cell proliferation in NSCLC through

interacting with HSPB-1

1
1
2
1
2
Wenyan Yang , Lin Yang , Qihan He , Peikun Ding , Zheng Wang , Lijuan Ling , Yi Song ,
2
2
Rihong Zhai 1
1 Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, China.
2 Shenzhen People’s Hospital, Shenzhen 518055, Guangdong, China.
Background: tRNA derived-fragments (tRFs) comprise a new class of non-coding small-molecule RNA.
Recent studies suggest that tRFs are involved in the development and progress of several cancers. However,
the impact of tRFs in non-small cell lung cancer (NSCLC) remains elusive.

Methods: NSCLC-related tRFs were determined by RNA-seq. Expression of tRFs in tumor tissues, plasma,
and NSCLC cell lines was analyzed with qRT-PCR. The effect of tRFs on NSCLC malignancy was evaluated
in vitro by loss- and gain-of-function assays. RNA-seq was conducted to screen for the target genes of tRFs.
The mechanism of action of tRFs was explored with RNA pulldown, RNA immunoprecipitation (RIP), and
qRT-PCR.