TY - JOUR
T1 - Combined inhibition of STAT3 and DNA repair in palbociclib-resistant er-positive breast cancer
AU - Kettner, Nicole M.
AU - Vijayaraghavan, Smruthi
AU - Durak, Merih Guray
AU - Bui, Tuyen
AU - Kohansal, Mehrnoosh
AU - Ha, Min Jin
AU - Liu, Bin
AU - Rao, Xiayu
AU - Wang, Jing
AU - Yi, Min
AU - Carey, Jason P.W.
AU - Chen, Xian
AU - Eckols, T. Kris
AU - Raghavendra, Akshara S.
AU - Ibrahim, Nuhad K.
AU - Karuturi, Meghan Sri
AU - Watowich, Stephanie S.
AU - Sahin, Aysegul
AU - Tweardy, David J.
AU - Hunt, Kelly K.
AU - Tripathy, Debu
AU - Keyomarsi, Khandan
N1 - Funding Information:
Research reported in this article was supported by the NCI of the NIH under award P30CA016672 to The University of Texas MD Anderson Cancer Center, the Department of Defense Breakthrough Post-Doctoral Fellowship BC170615 (to N.M. Kettner), R01 grant CA1522218, R01 grant CA223772, and Cancer Prevention and Research Institute of Texas (CPRIT) RP170079 grant (to K. Keyomarsi), CPRIT multi-investigator grant RP180712 (to K.K. Hunt and K. Keyomarsi), the Susan G. Komen for the Cure grant KG100521 (to K.K. Hunt), the Susan G. Komen post-doctoral fellowship grant PDF14302675 (to J.P.W. Carey), the CPRIT Research Training Program grant RP170067 (to S. Vijayaraghavan andN.M. Kettner), CPRIT grant DP150069 and V Foundation for Cancer Research Translational Research Award T2014-010 (to D.J. Tweardy), and NIH National Institute of Allergy and Infectious Diseases (NIAID) grant R01AI109294 (to S.S. Watowich).
Funding Information:
Research reported in this article was supported by the NCI of the NIH under award P30CA016672 to The University of Texas MD Anderson Cancer Center, the Department of Defense Breakthrough Post-Doctoral Fellowship BC170615 (to N.M. Kettner), R01 grant CA1522218, R01 grant CA223772, and Cancer Prevention and Research Institute of Texas (CPRIT) RP170079 grant (to K. Keyomarsi), CPRIT multi-investigator grant RP180712 (to K.K. Hunt and K. Keyomarsi), the Susan G. Komen for the Cure grant KG100521 (to K.K. Hunt), the Susan G. Komen post-doctoral fellowship grant PDF14302675 (to J.P.W. Carey), the CPRIT Research Training Program grant RP170067 (to S. Vijayaraghavan and N.M. Kettner), CPRIT grant DP150069 and V Foundation for Cancer Research Translational Research Award T2014-010 (to D.J. Tweardy), and NIH National Institute of Allergy and Infectious Diseases (NIAID) grant R01AI109294 (to S.S. Watowich).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are currently used in combination with endocrine therapy to treat advanced hormone receptor-positive, HER2-negative breast cancer. Although this treatment doubles time to progression compared with endocrine therapy alone, about 25%-35% of patients do not respond, and almost all patients eventually acquire resistance. Discerning the mechanisms of resistance to CDK4/6 inhibition is crucial in devising alternative treatment strategies. Experimental Design: Palbociclib-resistant cells (MCF-7 and T47D) were generated in a step-wise dose-escalading fashion. Whole-exome sequencing, genome-wide expression analysis, and proteomic analysis were performed in both resistant and parental (sensitive) cells. Pathway alteration was assessed mechanistically and pharmacologically. Biomarkers of altered pathways were examined in tumor samples from patients with palbociclib-treated breast cancer whose disease progressed while on treatment. Results: Palbociclib-resistant cells are cross-resistant to other CDK4/6 inhibitors and are also resistant to endocrine therapy (estrogen receptor downregulation). IL6/STAT3 pathway is induced, whereas DNA repair and estrogen receptor pathways are downregulated in the resistant cells. Combined inhibition of STAT3 and PARP significantly increased cell death in the resistant cells. Matched tumor samples from patients with breast cancer who progressed on palbociclib were examined for deregulation of estrogen receptor, DNA repair, and IL6/STAT3 signaling, and results revealed that these pathways are all altered as compared with the pretreatment tumor samples. Conclusions: Palbociclib resistance induces endocrine resistance, estrogen receptor downregulation, and alteration of IL6/STAT3 and DNA damage response pathways in cell lines and patient samples. Targeting IL6/STAT3 activity and DNA repair deficiency using a specific STAT3 inhibitor combined with a PARP inhibitor could effectively treat acquired resistance to palbociclib.
AB - Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are currently used in combination with endocrine therapy to treat advanced hormone receptor-positive, HER2-negative breast cancer. Although this treatment doubles time to progression compared with endocrine therapy alone, about 25%-35% of patients do not respond, and almost all patients eventually acquire resistance. Discerning the mechanisms of resistance to CDK4/6 inhibition is crucial in devising alternative treatment strategies. Experimental Design: Palbociclib-resistant cells (MCF-7 and T47D) were generated in a step-wise dose-escalading fashion. Whole-exome sequencing, genome-wide expression analysis, and proteomic analysis were performed in both resistant and parental (sensitive) cells. Pathway alteration was assessed mechanistically and pharmacologically. Biomarkers of altered pathways were examined in tumor samples from patients with palbociclib-treated breast cancer whose disease progressed while on treatment. Results: Palbociclib-resistant cells are cross-resistant to other CDK4/6 inhibitors and are also resistant to endocrine therapy (estrogen receptor downregulation). IL6/STAT3 pathway is induced, whereas DNA repair and estrogen receptor pathways are downregulated in the resistant cells. Combined inhibition of STAT3 and PARP significantly increased cell death in the resistant cells. Matched tumor samples from patients with breast cancer who progressed on palbociclib were examined for deregulation of estrogen receptor, DNA repair, and IL6/STAT3 signaling, and results revealed that these pathways are all altered as compared with the pretreatment tumor samples. Conclusions: Palbociclib resistance induces endocrine resistance, estrogen receptor downregulation, and alteration of IL6/STAT3 and DNA damage response pathways in cell lines and patient samples. Targeting IL6/STAT3 activity and DNA repair deficiency using a specific STAT3 inhibitor combined with a PARP inhibitor could effectively treat acquired resistance to palbociclib.
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U2 - 10.1158/1078-0432.CCR-18-3274
DO - 10.1158/1078-0432.CCR-18-3274
M3 - Article
C2 - 30867218
AN - SCOPUS:85068314505
SN - 1078-0432
VL - 25
SP - 3996
EP - 4013
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -