Amplification of TRIM44: pairing a prognostic target with potential therapeutic strategy.
BACKGROUND
Many prognostic biomarkers have been proposed recently. However, there is a lack of therapeutic strategies exploiting novel prognostic biomarkers. We aimed to propose therapeutic options in patients with overexpression of TRIM44, a recently identified prognostic gene.


METHODS
Genomic and transcriptomic data of epithelial cancers (n = 1932), breast cancers (BCs; n = 1980) and esophago-gastric cancers (EGCs; n = 163) were used to identify genomic aberrations driving TRIM44 overexpression. The driver gene status of TRIM44 was determined using a small interfering RNA (siRNA) screen of the 11p13 amplicon. Integrative analysis was applied across multiple datasets to identify pathway activation and potential therapeutic strategies. Validation of the in silico findings were performed using in vitro assays, xenografts, and patient samples (n = 160).


RESULTS
TRIM44 overexpression results from genomic amplification in 16.1% of epithelial cancers, including 8.1% of EGCs and 6.1% of BCs. This was confirmed using fluorescent in situ hybridization. The siRNA screen confirmed TRIM44 to be a driver of the amplicon. In silico analysis revealed an association between TRIM44 and mTOR signalling, supported by a decrease in mTOR signalling after siRNA knockdown of TRIM44 in cell lines and colocalization of TRIM44 and p-mTOR in patient samples. In vitro inhibition studies using an mTOR inhibitor (everolimus) decreased cell viability in two TRIM44-amplified cells lines by 88% and 70% compared with 35% in the control cell line. These findings were recapitulated in xenograft models.


CONCLUSIONS
Genomic amplification drives TRIM44 overexpression in EGCs and BCs. Targeting the mTOR pathway provides a potential therapeutic option for TRIM44-amplified tumors.
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Chin-Ann Johnny
CA
Ong
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Nicholas B
NB
Shannon
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Caryn S
CS
Ross-Innes
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Maria
M
O'Donovan
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Oscar M
OM
Rueda
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
De-En
DE
Hu
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Mikko I
MI
Kettunen
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Christina Elaine
CE
Walker
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Ayesha
A
Noorani
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Richard H
RH
Hardwick
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Carlos
C
Caldas
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
Kevin
K
Brindle
Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH). rcf29@hutchison-mrc.ac.uk.
Rebecca C
RC
Fitzgerald
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070584:Tripartite Motif Proteins
D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; C540677:TRIM44 protein, human; D000070584:Tripartite Motif Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases