Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer

Christine M. Lovly, Nerina T. McDonald, Heidi Chen, Sandra Ortiz-Cuaran, Lukas C. Heukamp, Yingjun Yan, Alexandra Florin, Luka Ozretić, Diana Lim, Lu Wang, Zhao Chen, Xi Chen, Pengcheng Lu, Paul K. Paik, Ronglai Shen, Hailing Jin, Reinhard Buettner, Sascha Ansén, Sven Perner, Michael Brockmann & 19 others Marc Bos, Jürgen Wolf, Masyar Gardizi, Gavin M. Wright, Benjamin Solomon, Prudence A. Russell, Toni Maree Rogers, Yoshiyuki Suehara, Monica Red-Brewer, Rudy Tieu, Elisa De Stanchina, Qingguo Wang, Zhongming Zhao, David H. Johnson, Leora Horn, Kwok Kin Wong, Roman K. Thomas, Marc Ladanyi, William Pao

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

Original languageEnglish (US)
Pages (from-to)1027-1034
Number of pages8
JournalNature Medicine
Volume20
Issue number9
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

Fingerprint

Somatomedin Receptors
Somatomedins
Lung Neoplasms
Fusion reactions
Insulin Receptor Substrate Proteins
Protein-Tyrosine Kinases
Gene encoding
Biopsy
Gene Fusion
Ports and harbors
Observation
Antibodies

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lovly, C. M., McDonald, N. T., Chen, H., Ortiz-Cuaran, S., Heukamp, L. C., Yan, Y., ... Pao, W. (2014). Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nature Medicine, 20(9), 1027-1034. https://doi.org/10.1038/nm.3667

Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. / Lovly, Christine M.; McDonald, Nerina T.; Chen, Heidi; Ortiz-Cuaran, Sandra; Heukamp, Lukas C.; Yan, Yingjun; Florin, Alexandra; Ozretić, Luka; Lim, Diana; Wang, Lu; Chen, Zhao; Chen, Xi; Lu, Pengcheng; Paik, Paul K.; Shen, Ronglai; Jin, Hailing; Buettner, Reinhard; Ansén, Sascha; Perner, Sven; Brockmann, Michael; Bos, Marc; Wolf, Jürgen; Gardizi, Masyar; Wright, Gavin M.; Solomon, Benjamin; Russell, Prudence A.; Rogers, Toni Maree; Suehara, Yoshiyuki; Red-Brewer, Monica; Tieu, Rudy; De Stanchina, Elisa; Wang, Qingguo; Zhao, Zhongming; Johnson, David H.; Horn, Leora; Wong, Kwok Kin; Thomas, Roman K.; Ladanyi, Marc; Pao, William.

In: Nature Medicine, Vol. 20, No. 9, 01.09.2014, p. 1027-1034.

Research output: Contribution to journalArticle

Lovly, CM, McDonald, NT, Chen, H, Ortiz-Cuaran, S, Heukamp, LC, Yan, Y, Florin, A, Ozretić, L, Lim, D, Wang, L, Chen, Z, Chen, X, Lu, P, Paik, PK, Shen, R, Jin, H, Buettner, R, Ansén, S, Perner, S, Brockmann, M, Bos, M, Wolf, J, Gardizi, M, Wright, GM, Solomon, B, Russell, PA, Rogers, TM, Suehara, Y, Red-Brewer, M, Tieu, R, De Stanchina, E, Wang, Q, Zhao, Z, Johnson, DH, Horn, L, Wong, KK, Thomas, RK, Ladanyi, M & Pao, W 2014, 'Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer', Nature Medicine, vol. 20, no. 9, pp. 1027-1034. https://doi.org/10.1038/nm.3667
Lovly CM, McDonald NT, Chen H, Ortiz-Cuaran S, Heukamp LC, Yan Y et al. Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nature Medicine. 2014 Sep 1;20(9):1027-1034. https://doi.org/10.1038/nm.3667
Lovly, Christine M. ; McDonald, Nerina T. ; Chen, Heidi ; Ortiz-Cuaran, Sandra ; Heukamp, Lukas C. ; Yan, Yingjun ; Florin, Alexandra ; Ozretić, Luka ; Lim, Diana ; Wang, Lu ; Chen, Zhao ; Chen, Xi ; Lu, Pengcheng ; Paik, Paul K. ; Shen, Ronglai ; Jin, Hailing ; Buettner, Reinhard ; Ansén, Sascha ; Perner, Sven ; Brockmann, Michael ; Bos, Marc ; Wolf, Jürgen ; Gardizi, Masyar ; Wright, Gavin M. ; Solomon, Benjamin ; Russell, Prudence A. ; Rogers, Toni Maree ; Suehara, Yoshiyuki ; Red-Brewer, Monica ; Tieu, Rudy ; De Stanchina, Elisa ; Wang, Qingguo ; Zhao, Zhongming ; Johnson, David H. ; Horn, Leora ; Wong, Kwok Kin ; Thomas, Roman K. ; Ladanyi, Marc ; Pao, William. / Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. In: Nature Medicine. 2014 ; Vol. 20, No. 9. pp. 1027-1034.
@article{722868059bf14694acb769ded5d6bfbc,
title = "Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer",
abstract = "Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.",
author = "Lovly, {Christine M.} and McDonald, {Nerina T.} and Heidi Chen and Sandra Ortiz-Cuaran and Heukamp, {Lukas C.} and Yingjun Yan and Alexandra Florin and Luka Ozretić and Diana Lim and Lu Wang and Zhao Chen and Xi Chen and Pengcheng Lu and Paik, {Paul K.} and Ronglai Shen and Hailing Jin and Reinhard Buettner and Sascha Ans{\'e}n and Sven Perner and Michael Brockmann and Marc Bos and J{\"u}rgen Wolf and Masyar Gardizi and Wright, {Gavin M.} and Benjamin Solomon and Russell, {Prudence A.} and Rogers, {Toni Maree} and Yoshiyuki Suehara and Monica Red-Brewer and Rudy Tieu and {De Stanchina}, Elisa and Qingguo Wang and Zhongming Zhao and Johnson, {David H.} and Leora Horn and Wong, {Kwok Kin} and Thomas, {Roman K.} and Marc Ladanyi and William Pao",
year = "2014",
month = "9",
day = "1",
doi = "10.1038/nm.3667",
language = "English (US)",
volume = "20",
pages = "1027--1034",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer

AU - Lovly, Christine M.

AU - McDonald, Nerina T.

AU - Chen, Heidi

AU - Ortiz-Cuaran, Sandra

AU - Heukamp, Lukas C.

AU - Yan, Yingjun

AU - Florin, Alexandra

AU - Ozretić, Luka

AU - Lim, Diana

AU - Wang, Lu

AU - Chen, Zhao

AU - Chen, Xi

AU - Lu, Pengcheng

AU - Paik, Paul K.

AU - Shen, Ronglai

AU - Jin, Hailing

AU - Buettner, Reinhard

AU - Ansén, Sascha

AU - Perner, Sven

AU - Brockmann, Michael

AU - Bos, Marc

AU - Wolf, Jürgen

AU - Gardizi, Masyar

AU - Wright, Gavin M.

AU - Solomon, Benjamin

AU - Russell, Prudence A.

AU - Rogers, Toni Maree

AU - Suehara, Yoshiyuki

AU - Red-Brewer, Monica

AU - Tieu, Rudy

AU - De Stanchina, Elisa

AU - Wang, Qingguo

AU - Zhao, Zhongming

AU - Johnson, David H.

AU - Horn, Leora

AU - Wong, Kwok Kin

AU - Thomas, Roman K.

AU - Ladanyi, Marc

AU - Pao, William

PY - 2014/9/1

Y1 - 2014/9/1

N2 - Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

AB - Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=84908363886&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908363886&partnerID=8YFLogxK

U2 - 10.1038/nm.3667

DO - 10.1038/nm.3667

M3 - Article

VL - 20

SP - 1027

EP - 1034

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 9

ER -