Skip to main content

Abstract 2703: Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106

Publication ,  Conference
Alwarawrah, Y; Hughes, P; Safi, R; McDonnell, DP; Spector, NL; Haystead, TA
Published in: Cancer Research
August 1, 2015

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that is overexpressed in about 20% of breast cancers and most often in the more aggressive inflammatory breast cancer (IBC). Lapatinib is one of the most potent small molecule inhibitors of HER2. Although Lapatinib has shown to be an effective targeted therapy, development of drug resistance stands as a major problem. Here we show that the anti-cancer activity of the novel fatty acid synthase inhibitor HS-106 can re-sensitize resistant cell lines to Lapatinib.Lapatinib resistant SKBR3 and BT474 breast cancer cell lines were treated with increasing concentrations of HS-106 either alone or in combination with Lapatinib and their effects on cell proliferation were assessed using the DNA dye Hoechst 33342. The ability of HS-106 and Lapatinib drug combination to induce apoptosis were measured in Caspase 3/7 activity assay using the fluorogenic Caspase substrate (DEVD)2 R110. Their effect on apoptosis was further confirmed in Lapatinib resistant BT474 cells using flow cytometry based Annexin V assay. In addition, the effect of HS-106 on the expression levels and phosphorylation of the kinases involved in Her2 pathway including Her2, AKT and ERK were determined. The fatty acid synthase inhibitor HS-106 significantly inhibits the proliferation of Lapatinib resistant cell lines with concentrations. Interestingly, when combined with Lapatinib, the drugs synergize to dramatically affect cell growth. This anti-proliferative activity of HS-106 was found to be the result of induction of apoptosis, Caspase 3/7 activity was found to increase in a dose dependent manner following HS-106 treatment. Low concentrations of Lapatinib and HS-106, which does not induce Caspase activity when administrated separately, were found to significantly induce Caspase activity when combined together. These results were confirmed with the Annexin V assay. By examining the expression levels of HER2 pathway proteins we found a decrease in HER2 levels which was reflected on the levels of the downstream kinases AKT and ERK when treating with high concentrations of HS-106.In a previous work, HS-106 showed a good tolerability and anti-cancer activity in the MMTV neu+ mouse model. By showing potent efficacy against Lapatinib resistant breast cancer cell lines, our data suggest that HS-106 is an excellent drug candidate to advance into translational studies for the treatment of Lapatinib resistant breast cancer.Citation Format: Yazan Alwarawrah, Philip Hughes, Rachid Safi, Donald P. McDonnell, Neil L. Spector, Timothy A. Haystead. Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2703. doi:10.1158/1538-7445.AM2015-2703

Duke Scholars

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

August 1, 2015

Volume

75

Issue

15_Supplement

Start / End Page

2703 / 2703

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Alwarawrah, Y., Hughes, P., Safi, R., McDonnell, D. P., Spector, N. L., & Haystead, T. A. (2015). Abstract 2703: Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106. In Cancer Research (Vol. 75, pp. 2703–2703). American Association for Cancer Research (AACR). https://doi.org/10.1158/1538-7445.am2015-2703
Alwarawrah, Yazan, Philip Hughes, Rachid Safi, Donald P. McDonnell, Neil L. Spector, and Timothy A. Haystead. “Abstract 2703: Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106.” In Cancer Research, 75:2703–2703. American Association for Cancer Research (AACR), 2015. https://doi.org/10.1158/1538-7445.am2015-2703.
Alwarawrah Y, Hughes P, Safi R, McDonnell DP, Spector NL, Haystead TA. Abstract 2703: Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106. In: Cancer Research. American Association for Cancer Research (AACR); 2015. p. 2703–2703.
Alwarawrah, Yazan, et al. “Abstract 2703: Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106.” Cancer Research, vol. 75, no. 15_Supplement, American Association for Cancer Research (AACR), 2015, pp. 2703–2703. Crossref, doi:10.1158/1538-7445.am2015-2703.
Alwarawrah Y, Hughes P, Safi R, McDonnell DP, Spector NL, Haystead TA. Abstract 2703: Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106. Cancer Research. American Association for Cancer Research (AACR); 2015. p. 2703–2703.

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

August 1, 2015

Volume

75

Issue

15_Supplement

Start / End Page

2703 / 2703

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis