Page 285 - 2014 Printable Abstract Book
P. 285
to 30 hours in conditioned media collected from young NHFs, suggesting that the aging-stroma confers
radioresistance of breast cancer cells. Overall, our results support the hypothesis that stromal-aging
promotes proliferation and confers radioresistance of breast cancer cells. (Supported by NIH 2R01
CA111365)
(PS4-87) Mitochondrial MKP1 is a target for radiotherapy-resistant HER2-positive breast cancer cells.
Demet Candas; Chung-Ling Lu; Ming Fan; Frank Y.S. Chuang; and Jian Jian Li, University of California, Davis,
Sacramento, CA
MKP1, a mitogen-activated protein kinase (MAPK) phosphatase, is overexpressed in
radioresistant breast cancer cells that are able to survive long-term radiation. Herein, MKP1 was found to
translocate into mitochondria upon radiation and target c-Jun N-terminal kinase (JNK), preventing the
initiation of apoptosis in both normal and tumor cells. This mitochondrial MKP1-driven survival
mechanism was predominantly adopted by HER2-overexpressing radioresistant breast cancer cells. In
clinic, MKP1 was exclusively expressed in HER2-positive breast tumor specimens, and MKP1 expression
was induced along with HER2 expression in tumors that have become HER2-positive during malignant
transformation of normal cells to tumor. Moreover, MKP1 was found to be overexpressed in irradiated
HER2-positive breast cancer stem cells (HER2+/CD44+/CD24-/low) while knock down of MKP1
substantially reduced their survival after irradiation. Combination of MKP1/HER2 inhibition considerably
enhanced the cell killing in breast cancer cells, when compared to HER2 inhibition or MKP1 inhibition
alone. Together, these findings identify a potential mechanism of radioresistance in breast tumors and
reveal MKP1 as a novel therapeutic target to sensitize resistant tumors and to improve efficacy of anti-
cancer therapies.
1
(PS4-88) Targeting NPM1 for the radiosensitization of NSCLC. Konjeti R. Sekhar, PhD ; Amudhan
2
2
1
Venkateswaran, PhD ; Narsimha R. Penthala, PhD ; Peter A. Crooks, PhD ; Stephen R. Hann, PhD ; Ling
1
3
4
1
1
Geng, PhD ; Ramesh Balusu, PhD ; Tarek Abbas, PhD ; Michael L. Freeman, PhD, Vanderbilt University,
1
2
Nashville,, TN ; University of Arkansas for Medical Sciences,, Little Rock, AR ; University of Kansas Cancer
4
3
Center, Kansas City, KS ; and University of Virginia School of Medicine, Charlotteville,, VA
There is an urgent need for the development of new strategies that improve therapeutic
outcomes for the treatment of NSCLC. YTR107 is a substituted 5-((N-benzyl-1H-indol-3-yl) methylene)
pyrimidine-2, 4, 6(1H, 3H, 5H) trione that amplifies replication stress and inhibits repair of DNA DSBs.
Nucleophosmin is a chaperone involved in many cellular functions including RAD51-mediated
homologous recombination. YTR107 targets NPM1 function impairing NPM1 oligomerization. The goal of
this investigation was to demonstrate that the specific targeting of NPM1 is a radiosensitizing event in
NSCLC. We employed a defined genetic model consisting of NPM1 null and wild type mouse embryo
fibroblasts (MEFs). We found that NPM1-null mouse embryo fibroblasts (MEFs) exhibit impaired DNA DSB
repair, as measured by formation and resolution of γH2AX foci, RAD51 foci and neutral comet assays.
Because the DNA damage response pathway is continuously activated in NSCLC in response to constant
replication stress, and with the knowledge that NPM1 expression minimizes such stress, we hypothesized
that NSCLC tumors might require significant expression of NPM1. This hypothesis was validated by
analyzing a NSCLC tumor microarray. We then showed that YTR107-mediated targeting of NPM1 is a
283 | P a g e
radioresistance of breast cancer cells. Overall, our results support the hypothesis that stromal-aging
promotes proliferation and confers radioresistance of breast cancer cells. (Supported by NIH 2R01
CA111365)
(PS4-87) Mitochondrial MKP1 is a target for radiotherapy-resistant HER2-positive breast cancer cells.
Demet Candas; Chung-Ling Lu; Ming Fan; Frank Y.S. Chuang; and Jian Jian Li, University of California, Davis,
Sacramento, CA
MKP1, a mitogen-activated protein kinase (MAPK) phosphatase, is overexpressed in
radioresistant breast cancer cells that are able to survive long-term radiation. Herein, MKP1 was found to
translocate into mitochondria upon radiation and target c-Jun N-terminal kinase (JNK), preventing the
initiation of apoptosis in both normal and tumor cells. This mitochondrial MKP1-driven survival
mechanism was predominantly adopted by HER2-overexpressing radioresistant breast cancer cells. In
clinic, MKP1 was exclusively expressed in HER2-positive breast tumor specimens, and MKP1 expression
was induced along with HER2 expression in tumors that have become HER2-positive during malignant
transformation of normal cells to tumor. Moreover, MKP1 was found to be overexpressed in irradiated
HER2-positive breast cancer stem cells (HER2+/CD44+/CD24-/low) while knock down of MKP1
substantially reduced their survival after irradiation. Combination of MKP1/HER2 inhibition considerably
enhanced the cell killing in breast cancer cells, when compared to HER2 inhibition or MKP1 inhibition
alone. Together, these findings identify a potential mechanism of radioresistance in breast tumors and
reveal MKP1 as a novel therapeutic target to sensitize resistant tumors and to improve efficacy of anti-
cancer therapies.
1
(PS4-88) Targeting NPM1 for the radiosensitization of NSCLC. Konjeti R. Sekhar, PhD ; Amudhan
2
2
1
Venkateswaran, PhD ; Narsimha R. Penthala, PhD ; Peter A. Crooks, PhD ; Stephen R. Hann, PhD ; Ling
1
3
4
1
1
Geng, PhD ; Ramesh Balusu, PhD ; Tarek Abbas, PhD ; Michael L. Freeman, PhD, Vanderbilt University,
1
2
Nashville,, TN ; University of Arkansas for Medical Sciences,, Little Rock, AR ; University of Kansas Cancer
4
3
Center, Kansas City, KS ; and University of Virginia School of Medicine, Charlotteville,, VA
There is an urgent need for the development of new strategies that improve therapeutic
outcomes for the treatment of NSCLC. YTR107 is a substituted 5-((N-benzyl-1H-indol-3-yl) methylene)
pyrimidine-2, 4, 6(1H, 3H, 5H) trione that amplifies replication stress and inhibits repair of DNA DSBs.
Nucleophosmin is a chaperone involved in many cellular functions including RAD51-mediated
homologous recombination. YTR107 targets NPM1 function impairing NPM1 oligomerization. The goal of
this investigation was to demonstrate that the specific targeting of NPM1 is a radiosensitizing event in
NSCLC. We employed a defined genetic model consisting of NPM1 null and wild type mouse embryo
fibroblasts (MEFs). We found that NPM1-null mouse embryo fibroblasts (MEFs) exhibit impaired DNA DSB
repair, as measured by formation and resolution of γH2AX foci, RAD51 foci and neutral comet assays.
Because the DNA damage response pathway is continuously activated in NSCLC in response to constant
replication stress, and with the knowledge that NPM1 expression minimizes such stress, we hypothesized
that NSCLC tumors might require significant expression of NPM1. This hypothesis was validated by
analyzing a NSCLC tumor microarray. We then showed that YTR107-mediated targeting of NPM1 is a
283 | P a g e
