In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 5455-5455
Abstract:
Receptor tyrosine kinases (RTKs) constitute the largest family of structurally related oncogenes and are often involved in the initiation, maintenance and/or metastasis of various human cancers. The genes encoding RTKs are frequently amplified, fused, mutated, or the ligands are expressed at high levels, causing abnormal activation and downstream signaling. Two major types of drugs have been used with success to treat cancers with abnormal RTK activation, recombinant monoclonal antibodies (mAbs) and small molecule inhibitors of the tyrosine kinases (TKIs). TKIs have proven most successful against cancers driven by gene fusions or mutations, whereas mAbs dominate in cancers driven by gene amplifications or ligand-mediated RTK activation. Recent studies show that the two types of treatment modalities may often be synergistic, but the reason for this is not well characterized. Here, we demonstrate that surface levels of various RTKs increase in cancer cell lines upon treatment with TKIs specific for the individual RTKs. The effect was most pronounced in cell lines with amplification or autocrine ligand production and occurred at inhibitor concentrations suboptimal for inhibition of growth. Removal of the TKIs resulted in an increase in RTK activity and cancer cell proliferation as a result of the increased RTK levels. MAbs, especially mAb mixtures, when given in combination with the TKIs were found to prevent RTK accumulation and led to enhanced efficacy. Due to the increased number of receptors, the combination also resulted in enhancement of secondary effector functions, such as ADCC. In conclusion, our results demonstrate that in certain contexts TKI treatment leads to RTK accumulation and that this accumulation has the potential to enhance tumor growth. Antibody mixtures, when given together with the TKIs, can prevent RTK accumulation and even enhance the TKI activity. Citation Format: Anne-Mette Bjerregaard, Michael V. Grandal, Camilla Frohlich, Trine Lindsted, Christina Egebjerg, Ivan D. Horac, Michael Kragh, Mikkel W. Pedersen. Surface accumulation of receptor tyrosine kinases upon treatment with tyrosine kinase inhibitors and resulting enhancement of activity upon treatment cessation. [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 5455. doi:10.1158/1538-7445.AM2015-5455
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-5455
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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