Dual targeting of IGF-1R and ErbB3 as a potential therapeutic regimen for ovarian cancer

被引：17

作者：

Camblin, Adam J. ^{[1
]}

Tan, Gege ^{[1
]}

Curley, Michael D. ^{[1
]}

Yannatos, Isabel ^{[1
]}

Iadevaia, Sergio ^{[1
]}

Rimkunas, Victoria ^{[1
]}

Mino-Kenudson, Mari ^{[2
]}

Bloom, Troy ^{[1
]}

Schoeberl, Birgit ^{[1
]}

Drummond, Daryl C. ^{[1
]}

Lugovskoy, Alexey A. ^{[1
]}

Louis, Chrystal U. ^{[1
]}

Askoxylakis, Vasileios ^{[1
]}

机构：

[1] Merrimack Pharmaceut Inc, Cambridge, MA 02142 USA

[2] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

关键词：

GROWTH-FACTOR-I; PLATINUM-RESISTANT; EXPRESSION; RECEPTOR; ANTIBODY; TRIAL; PROLIFERATION; COMBINATION; INHIBITION; SURVIVAL;

D O I：

10.1038/s41598-019-53322-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Therapeutically targeting receptor tyrosine kinases has proven to be paramount to overcoming chemotherapy resistance in several cancer indications, improving patient outcomes. Insulin-Like Growth Factor Receptor 1 (IGF-1R) and Epidermal Growth Factor Receptor 3 (ErbB3) have been implicated as two such drivers of resistance, however their simultaneous role in ovarian cancer chemotherapy resistance remains poorly elucidated. The aim of this work is to determine the effects of dual IGF-1R/ErbB3 inhibition on ovarian cancer cell signaling, growth, and in vivo efficacy. Assessment of in vitro chemotherapy response across a panel of ovarian cancer cell lines revealed that increased IGF-1R cell surface expression correlates with decreased sensitivity to chemotherapy, and that growth induced by IGF-1R and ErbB3 ligands is blocked by the tetravalent bispecific antibody targeting IGF-1R and ErbB3, istiratumab. In vitro chemotherapy treatment increased ovarian cancer cell line capacity to activate prosurvival PI3K signaling in response to ligand, which could be prevented with istiratumab treatment. Furthermore, in vivo efficacy of standard of care chemotherapies using a xenograft model of ovarian cancer was potentiated with istiratumab. Our results suggest a role for IGF-1R and ErbB3 in driving chemotherapy resistance of ovarian cancer.

引用

页数：10

共 36 条

[1]

[Anonymous], ESMO 2018 C

[2]

[Anonymous], 2013, ASCO ANN M

[3] ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics [J].

Arteaga, Carlos L. ;

Engelman, Jeffrey A. .

CANCER CELL, 2014, 25 (03) :282-303

[4] Ganitumab (AMG 479) Inhibits IGF-II-Dependent Ovarian Cancer Growth and Potentiates Platinum-Based Chemotherapy [J].

Beltran, Pedro J. ;

Calzone, Frank J. ;

Mitchell, Petia ;

Chung, Young-Ah ;

Cajulis, Elaina ;

Moody, Gordon ;

Belmontes, Brian ;

Li, Chi-Ming ;

Vonderfecht, Steven ;

Velculescu, Victor E. ;

Yang, Guorong ;

Qi, Jingwei ;

Slamon, Dennis J. ;

Konecny, Gottfried E. .

CLINICAL CANCER RESEARCH, 2014, 20 (11) :2947-2958

[5] A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours [J].

Brana, I. ;

Berger, R. ;

Golan, T. ;

Haluska, P. ;

Edenfield, J. ;

Fiorica, J. ;

Stephenson, J. ;

Martin, L. P. ;

Westin, S. ;

Hanjani, P. ;

Jones, M. B. ;

Almhanna, K. ;

Wenham, R. M. ;

Sullivan, D. M. ;

Dalton, W. S. ;

Gunchenko, A. ;

Cheng, J. D. ;

Siu, L. L. ;

Gray, J. E. .

BRITISH JOURNAL OF CANCER, 2014, 111 (10) :1932-1944

[6] Targeting IGF-1 signaling pathways in gynecologic malignancies [J].

Bruchim, Ilan ;

Werner, Haim .

EXPERT OPINION ON THERAPEUTIC TARGETS, 2013, 17 (03) :307-320

[7] Dual Inhibition of IGF-1R and ErbB3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer [J].

Camblin, Adam J. ;

Pace, Emily A. ;

Adams, Sharlene ;

Curley, Michael D. ;

Rimkunas, Victoria ;

Nie, Lin ;

Tan, Gege ;

Bloom, Troy ;

Ladevaia, Sergio ;

Baum, Jason ;

Minx, Charlene ;

Czibere, Akos ;

Louis, Chrystal U. ;

Drummond, Daryl C. ;

Nielsen, Ulrik B. ;

Schoeberl, Birgit ;

Pipas, J. Marc ;

Straubinger, Robert M. ;

Askoxylakis, Vasileios ;

Lugovskoy, Alexey A. .

CLINICAL CANCER RESEARCH, 2018, 24 (12) :2873-2885

[8] Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer [J].

Campos, S ;

Hamid, C ;

Seiden, MV ;

Oza, A ;

Plante, M ;

Potkul, RK ;

Lenehan, PF ;

Kaldjian, EP ;

Varterasian, ML ;

Jordan, C ;

Charbonneau, C ;

Hirte, H .

JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (24) :5597-5604

[9] High Incidence of ErbB3, ErbB4, and MET Expression in Ovarian Cancer [J].

Davies, Suzy ;

Holmes, Anna ;

Lomo, Lesley ;

Steinkamp, Mara P. ;

Kang, Huining ;

Muller, Carolyn Y. ;

Wilson, Bridget S. .

INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY, 2014, 33 (04) :402-410

[10] Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers [J].

Drilon, Alexander ;

Somwar, Romel ;

Mangatt, Biju P. ;

Edgren, Henrik ;

Desmeules, Patrice ;

Ruusulehto, Anja ;

Smith, Roger S. ;

Delasos, Lukas ;

Vojnic, Morana ;

Plodkowski, Andrew J. ;

Sabari, Joshua ;

Ng, Kenneth ;

Montecalvo, Joseph ;

Chang, Jason ;

Tai, Huichun ;

Lockwood, William W. ;

Martinez, Victor ;

Riely, Gregory J. ;

Rudin, Charles M. ;

Kris, Mark G. ;

Arcila, Maria E. ;

Matheny, Christopher ;

Benayed, Ryma ;

Rekhtman, Natasha ;

Ladanyi, Marc ;

Ganji, Gopinath .

CANCER DISCOVERY, 2018, 8 (06) :686-695

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