TY - JOUR
T1 - Arginine starvation and docetaxel induce c-Myc–driven HENT1 surface expression to overcome gemcitabine resistance in AsS1-negative tumors
AU - Prudner, Bethany C.
AU - Rathore, Richa
AU - Robinson, Anthony M.
AU - Godec, Abigail
AU - Chang, Samuel F.
AU - Hawkins, William G.
AU - Hirbe, Angela C.
AU - Van Tine, Brian A.
N1 - Funding Information:
B.A. Van Tine reports receiving commercial research grants from Merck, Pfizer, and Tracon; reports receiving speakers bureau honoraria from Lilly, Janssen, and Caris; is a consultant/advisory board member for Epizyme, Lilly, CytRx, Janssen, Immune Design, Daiichi, Plexxicon, and Adaptimmune; and reports receiving other remuneration from Lilly. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This project was supported by grants from CJ's Journey (B.C. Prudner, R. Rathore, A.M. Robinson, S.F. Chang, B.A. Van Tine), The Sarcoma Foundation of America (B.C. Prudner, B.A. Van Tine), The Sarcoma Alliance For Research and Collaboration (SARC); (B.A. Van Tine) and Siteman Cancer Center Investment Program (funded by the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund and Barnard Trust) (B.C. Prudner, R. Rathore, A.M. Robinson, S.F. Chang, B.A. Van Tine).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/8/15
Y1 - 2019/8/15
N2 - Purpose: The response to acute and long-term arginine starvation results in a conditional adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. Here, we investigate the underlying biology of priming ASS1 tumors with arginine deiminase (ADI-PEG20) before treatment with gemcitabine (GEM) and docetaxel (DTX) in sarcoma, pancreatic cancer, and melanoma cell lines. Experimental Design: ASS1 tumor cell lines were treated to create LTAT (long-term ADI treated) cell lines (ASS1þ) and used for drug combination studies. Protein expression of ASS1, dCK, RRM2, E2F1, c-MYC, and hENT1 was measured. c-MYC activity was determined, live-cell immunofluorescent studies for hENT1, uptake assays of FITC-cytosine probe, and rescue studies with a c-MYC inhibitor were all determined in the presence or absence of the ADI-PEG20:GEM:DTX. Results: In examining modulations within the pyrimidine pathway, we identified that the addition of DTX to cells treated with ADI-PEG20 resulted in translocation of stabilized c-Myc to the nucleus. This resulted in an increase of hENT1 cell-surface expression and rendered the cells susceptible to GEM. In vivo studies demonstrate that the combination of ADI-PEG20:GEM: DTX was optimal for tumor growth inhibition, providing the preclinical mechanism and justification for the ongoing clinical trial of ADI-PEG20, GEM, and DTX in sarcoma. Conclusions: The priming of tumors with ADI-PEG20 and DTX results in the stabilization of c-MYC potentiating the effect of GEM treatment via an increase in hENT1 expression. This finding is applicable to ASS1-deficient cancers that are currently treated with GEM.
AB - Purpose: The response to acute and long-term arginine starvation results in a conditional adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. Here, we investigate the underlying biology of priming ASS1 tumors with arginine deiminase (ADI-PEG20) before treatment with gemcitabine (GEM) and docetaxel (DTX) in sarcoma, pancreatic cancer, and melanoma cell lines. Experimental Design: ASS1 tumor cell lines were treated to create LTAT (long-term ADI treated) cell lines (ASS1þ) and used for drug combination studies. Protein expression of ASS1, dCK, RRM2, E2F1, c-MYC, and hENT1 was measured. c-MYC activity was determined, live-cell immunofluorescent studies for hENT1, uptake assays of FITC-cytosine probe, and rescue studies with a c-MYC inhibitor were all determined in the presence or absence of the ADI-PEG20:GEM:DTX. Results: In examining modulations within the pyrimidine pathway, we identified that the addition of DTX to cells treated with ADI-PEG20 resulted in translocation of stabilized c-Myc to the nucleus. This resulted in an increase of hENT1 cell-surface expression and rendered the cells susceptible to GEM. In vivo studies demonstrate that the combination of ADI-PEG20:GEM: DTX was optimal for tumor growth inhibition, providing the preclinical mechanism and justification for the ongoing clinical trial of ADI-PEG20, GEM, and DTX in sarcoma. Conclusions: The priming of tumors with ADI-PEG20 and DTX results in the stabilization of c-MYC potentiating the effect of GEM treatment via an increase in hENT1 expression. This finding is applicable to ASS1-deficient cancers that are currently treated with GEM.
UR - http://www.scopus.com/inward/record.url?scp=85070662733&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-0206
DO - 10.1158/1078-0432.CCR-19-0206
M3 - Article
C2 - 31113844
AN - SCOPUS:85070662733
SN - 1078-0432
VL - 25
SP - 5122
EP - 5134
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -