Src family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma

Yoshihiro Tokuhisa, Michael E. Lidsky, Hiroaki Toshimitsu, Ryan S. Turley, Georgia M. Beasley, Tomio Ueno, Ketan Sharma, Christina K. Augustine, Douglas Tyler

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma. Methods: The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130CAS), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft. Results: Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days). Conclusions: Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.

Original languageEnglish (US)
Pages (from-to)1024-1030
Number of pages7
JournalAnnals of Surgical Oncology
Volume21
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

Fingerprint

Melphalan
src-Family Kinases
Melanoma
Extremities
Drug Therapy
Heterografts
Cell Line
Crk-Associated Substrate Protein
Gene Expression
Focal Adhesion Protein-Tyrosine Kinases
Dasatinib
Alkylating Agents
Neoplasms
Cell Survival
Clinical Trials
Mutation
Therapeutics

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Src family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma. / Tokuhisa, Yoshihiro; Lidsky, Michael E.; Toshimitsu, Hiroaki; Turley, Ryan S.; Beasley, Georgia M.; Ueno, Tomio; Sharma, Ketan; Augustine, Christina K.; Tyler, Douglas.

In: Annals of Surgical Oncology, Vol. 21, No. 3, 03.2014, p. 1024-1030.

Research output: Contribution to journalArticle

Tokuhisa, Y, Lidsky, ME, Toshimitsu, H, Turley, RS, Beasley, GM, Ueno, T, Sharma, K, Augustine, CK & Tyler, D 2014, 'Src family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma', Annals of Surgical Oncology, vol. 21, no. 3, pp. 1024-1030. https://doi.org/10.1245/s10434-013-3387-6
Tokuhisa, Yoshihiro ; Lidsky, Michael E. ; Toshimitsu, Hiroaki ; Turley, Ryan S. ; Beasley, Georgia M. ; Ueno, Tomio ; Sharma, Ketan ; Augustine, Christina K. ; Tyler, Douglas. / Src family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma. In: Annals of Surgical Oncology. 2014 ; Vol. 21, No. 3. pp. 1024-1030.
@article{50b33d24227641d8922e3808addcd74a,
title = "Src family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma",
abstract = "Background: Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma. Methods: The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130CAS), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft. Results: Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days). Conclusions: Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.",
author = "Yoshihiro Tokuhisa and Lidsky, {Michael E.} and Hiroaki Toshimitsu and Turley, {Ryan S.} and Beasley, {Georgia M.} and Tomio Ueno and Ketan Sharma and Augustine, {Christina K.} and Douglas Tyler",
year = "2014",
month = "3",
doi = "10.1245/s10434-013-3387-6",
language = "English (US)",
volume = "21",
pages = "1024--1030",
journal = "Annals of Surgical Oncology",
issn = "1068-9265",
publisher = "Springer New York",
number = "3",

}

TY - JOUR

T1 - Src family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma

AU - Tokuhisa, Yoshihiro

AU - Lidsky, Michael E.

AU - Toshimitsu, Hiroaki

AU - Turley, Ryan S.

AU - Beasley, Georgia M.

AU - Ueno, Tomio

AU - Sharma, Ketan

AU - Augustine, Christina K.

AU - Tyler, Douglas

PY - 2014/3

Y1 - 2014/3

N2 - Background: Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma. Methods: The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130CAS), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft. Results: Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days). Conclusions: Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.

AB - Background: Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma. Methods: The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130CAS), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft. Results: Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days). Conclusions: Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.

UR - http://www.scopus.com/inward/record.url?scp=84896731491&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896731491&partnerID=8YFLogxK

U2 - 10.1245/s10434-013-3387-6

DO - 10.1245/s10434-013-3387-6

M3 - Article

C2 - 24281418

AN - SCOPUS:84896731491

VL - 21

SP - 1024

EP - 1030

JO - Annals of Surgical Oncology

JF - Annals of Surgical Oncology

SN - 1068-9265

IS - 3

ER -