ALK inhibitor PF02341066 (Crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK

Yunguang Sun, Kamila A. Nowak, Nicholas Zaorsky, Chia Lin Winchester, Kunal Dalal, Nicholas J. Giacalone, Ningbo Liu, Maria Werner-Wasik, Mariusz A. Wasik, Adam P. Dicker, Bo Lu

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Crizotinib (PF02341066) is a tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that has been shown to selectively inhibit growth of cancer cells that harbor the EML4-ALK fusion found in a subset of patients with non-small cell lung cancer (NSCLC). While in clinical trials, PF02341066 has shown a significant therapeutic benefit as a single agent; the effectiveness of combining it with other therapeutic modalities including ionizing radiation remains unknown. To further elucidate the role of PF02341066 in tumor inhibition, we examined its effects alone and in combination with radiation on downstream signaling, apoptosis, and radiosensitivity in two NSCLC cell lines in vitro: H3122, which harbors the EML4-ALK fusion, and H460, which does not. We also examined the in vivo effects of PF02341066 in H3122 mouse xenografts. In the H3122 cell line, PF02341066 inhibited phosphorylation of ALK and its downstream effectors: AKT, ERK, and STAT3. H3122 cells treated with a combination of PF02341066 and radiation showed an increase in cellular apoptosis and were sensitized to radiation therapy (dose enhancement ratio, 1.43; P < 0.0001). Moreover, in an H3122 xenograft model, the combined treatment resulted in greater tumor growth inhibition than either treatment alone (P < 0.05). None of these effects was observed in the EML4-ALK-negative H460 cells. Our findings indicate that PF02341066 acts as a radiation sensitizer in cells harboring the EML4-ALK fusion, providing a rationale for a clinical trial combining ALK inhibitor with radiation in the NSCLCs expressing ALK.

Original languageEnglish (US)
Pages (from-to)696-704
Number of pages9
JournalMolecular cancer therapeutics
Volume12
Issue number5
DOIs
StatePublished - May 1 2013

Fingerprint

Radiation Tolerance
Non-Small Cell Lung Carcinoma
Radiation
Heterografts
Clinical Trials
Apoptosis
Radiation-Sensitizing Agents
Cell Line
Neoplasms
anaplastic lymphoma kinase
crizotinib
Therapeutics
Growth
Ionizing Radiation
Protein-Tyrosine Kinases
Radiotherapy
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Sun, Yunguang ; Nowak, Kamila A. ; Zaorsky, Nicholas ; Winchester, Chia Lin ; Dalal, Kunal ; Giacalone, Nicholas J. ; Liu, Ningbo ; Werner-Wasik, Maria ; Wasik, Mariusz A. ; Dicker, Adam P. ; Lu, Bo. / ALK inhibitor PF02341066 (Crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK. In: Molecular cancer therapeutics. 2013 ; Vol. 12, No. 5. pp. 696-704.
@article{c28dd7da372f41ee8e44400f18dba1f2,
title = "ALK inhibitor PF02341066 (Crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK",
abstract = "Crizotinib (PF02341066) is a tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that has been shown to selectively inhibit growth of cancer cells that harbor the EML4-ALK fusion found in a subset of patients with non-small cell lung cancer (NSCLC). While in clinical trials, PF02341066 has shown a significant therapeutic benefit as a single agent; the effectiveness of combining it with other therapeutic modalities including ionizing radiation remains unknown. To further elucidate the role of PF02341066 in tumor inhibition, we examined its effects alone and in combination with radiation on downstream signaling, apoptosis, and radiosensitivity in two NSCLC cell lines in vitro: H3122, which harbors the EML4-ALK fusion, and H460, which does not. We also examined the in vivo effects of PF02341066 in H3122 mouse xenografts. In the H3122 cell line, PF02341066 inhibited phosphorylation of ALK and its downstream effectors: AKT, ERK, and STAT3. H3122 cells treated with a combination of PF02341066 and radiation showed an increase in cellular apoptosis and were sensitized to radiation therapy (dose enhancement ratio, 1.43; P < 0.0001). Moreover, in an H3122 xenograft model, the combined treatment resulted in greater tumor growth inhibition than either treatment alone (P < 0.05). None of these effects was observed in the EML4-ALK-negative H460 cells. Our findings indicate that PF02341066 acts as a radiation sensitizer in cells harboring the EML4-ALK fusion, providing a rationale for a clinical trial combining ALK inhibitor with radiation in the NSCLCs expressing ALK.",
author = "Yunguang Sun and Nowak, {Kamila A.} and Nicholas Zaorsky and Winchester, {Chia Lin} and Kunal Dalal and Giacalone, {Nicholas J.} and Ningbo Liu and Maria Werner-Wasik and Wasik, {Mariusz A.} and Dicker, {Adam P.} and Bo Lu",
year = "2013",
month = "5",
day = "1",
doi = "10.1158/1535-7163.MCT-12-0868",
language = "English (US)",
volume = "12",
pages = "696--704",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

Sun, Y, Nowak, KA, Zaorsky, N, Winchester, CL, Dalal, K, Giacalone, NJ, Liu, N, Werner-Wasik, M, Wasik, MA, Dicker, AP & Lu, B 2013, 'ALK inhibitor PF02341066 (Crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK', Molecular cancer therapeutics, vol. 12, no. 5, pp. 696-704. https://doi.org/10.1158/1535-7163.MCT-12-0868

ALK inhibitor PF02341066 (Crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK. / Sun, Yunguang; Nowak, Kamila A.; Zaorsky, Nicholas; Winchester, Chia Lin; Dalal, Kunal; Giacalone, Nicholas J.; Liu, Ningbo; Werner-Wasik, Maria; Wasik, Mariusz A.; Dicker, Adam P.; Lu, Bo.

In: Molecular cancer therapeutics, Vol. 12, No. 5, 01.05.2013, p. 696-704.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ALK inhibitor PF02341066 (Crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK

AU - Sun, Yunguang

AU - Nowak, Kamila A.

AU - Zaorsky, Nicholas

AU - Winchester, Chia Lin

AU - Dalal, Kunal

AU - Giacalone, Nicholas J.

AU - Liu, Ningbo

AU - Werner-Wasik, Maria

AU - Wasik, Mariusz A.

AU - Dicker, Adam P.

AU - Lu, Bo

PY - 2013/5/1

Y1 - 2013/5/1

N2 - Crizotinib (PF02341066) is a tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that has been shown to selectively inhibit growth of cancer cells that harbor the EML4-ALK fusion found in a subset of patients with non-small cell lung cancer (NSCLC). While in clinical trials, PF02341066 has shown a significant therapeutic benefit as a single agent; the effectiveness of combining it with other therapeutic modalities including ionizing radiation remains unknown. To further elucidate the role of PF02341066 in tumor inhibition, we examined its effects alone and in combination with radiation on downstream signaling, apoptosis, and radiosensitivity in two NSCLC cell lines in vitro: H3122, which harbors the EML4-ALK fusion, and H460, which does not. We also examined the in vivo effects of PF02341066 in H3122 mouse xenografts. In the H3122 cell line, PF02341066 inhibited phosphorylation of ALK and its downstream effectors: AKT, ERK, and STAT3. H3122 cells treated with a combination of PF02341066 and radiation showed an increase in cellular apoptosis and were sensitized to radiation therapy (dose enhancement ratio, 1.43; P < 0.0001). Moreover, in an H3122 xenograft model, the combined treatment resulted in greater tumor growth inhibition than either treatment alone (P < 0.05). None of these effects was observed in the EML4-ALK-negative H460 cells. Our findings indicate that PF02341066 acts as a radiation sensitizer in cells harboring the EML4-ALK fusion, providing a rationale for a clinical trial combining ALK inhibitor with radiation in the NSCLCs expressing ALK.

AB - Crizotinib (PF02341066) is a tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that has been shown to selectively inhibit growth of cancer cells that harbor the EML4-ALK fusion found in a subset of patients with non-small cell lung cancer (NSCLC). While in clinical trials, PF02341066 has shown a significant therapeutic benefit as a single agent; the effectiveness of combining it with other therapeutic modalities including ionizing radiation remains unknown. To further elucidate the role of PF02341066 in tumor inhibition, we examined its effects alone and in combination with radiation on downstream signaling, apoptosis, and radiosensitivity in two NSCLC cell lines in vitro: H3122, which harbors the EML4-ALK fusion, and H460, which does not. We also examined the in vivo effects of PF02341066 in H3122 mouse xenografts. In the H3122 cell line, PF02341066 inhibited phosphorylation of ALK and its downstream effectors: AKT, ERK, and STAT3. H3122 cells treated with a combination of PF02341066 and radiation showed an increase in cellular apoptosis and were sensitized to radiation therapy (dose enhancement ratio, 1.43; P < 0.0001). Moreover, in an H3122 xenograft model, the combined treatment resulted in greater tumor growth inhibition than either treatment alone (P < 0.05). None of these effects was observed in the EML4-ALK-negative H460 cells. Our findings indicate that PF02341066 acts as a radiation sensitizer in cells harboring the EML4-ALK fusion, providing a rationale for a clinical trial combining ALK inhibitor with radiation in the NSCLCs expressing ALK.

UR - http://www.scopus.com/inward/record.url?scp=84877672976&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877672976&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-12-0868

DO - 10.1158/1535-7163.MCT-12-0868

M3 - Article

VL - 12

SP - 696

EP - 704

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 5

ER -