Abstract P6-02-01: Elucidating the change of TRAIL sensitivity in basal like TNBC cell lines by lapatinib, and further therapeutic implication

Abstract

Abstract Triple negative breast cancer (TNBC) comprises 15-20% of breast cancer, and carries a poor prognosis. Recently, efforts to understand this heterogeneous group of cancers have led to recognition of different subtypes of TNBC by Dr. Pietenpol et al based on genetic and functional signature. So far, the only targeting agent for TNBC still remains as androgen receptor inhibitor for LAR group. Thus, other strategies in therapeutic development for TNBCs are necessary. TRAIL (Tumor Necrosis Factor-related apoptosis inducing ligand), a member of the TNF-alpha family of death receptor ligands, induces apoptosis by binding death receptors (DR4 and DR5), could be a good strategy in therapeutic development in TNBC. Unfortunately, majority of breast cancer cell lines are resistant to TRAIL targeted therapy especially basal like group of cells, as previously shown in the work of Lipkowitz at the NCI. Lapatinib, a well known as erbB 1 and 2 inhibitor had been found to have off target activity inducing JNK, an important activator of nuclear transcription of death receptor, and mitochondrial mediated intrinsic apoptosis pathway. Interestingly, study of combination therapy with lapatinib and TRAIL not only confirmed baseline poor sensitivity to TRAIL induced apoptosis in “basal like” HCC 1937 and MDA-MB-468 cell lines, but also revealed an unexpected difference in sensitization to TRAIL induced apoptosis by Lapatinib pre-treatment between these two cell lines. When treated with 48hrs Lapatinib high–dose treatment, HCC 1937 showed increased sensitization whereas MDA-MB-468 did not. Both HCC 1937 and MDA-MB-468 are in the same basal like 1(BL1) group by Dr. Pietenpol's analysis, and their baseline sensitivity to TRAIL inducing apoptosis are the same. In terms of apoptosis - there are two big categories of cells. Type I cells are independent of mitochondria for the induction of Fas death receptor mediated apoptosis, where as type II cells are mitochrondria-dependent. Thus we hypothesized that this difference in lapatinib induced TRAIL sensitization between two cell lines is due to difference in one being type I vs the other being type II cell, and this type of apoptosis is not likely equal in same subgroup of TNBC. If this hypothesis is correct, targeting apoptosis pathway in TNBC should incorporate the recognition of apoptosis cell types rather than functional/genetic based subtypes. We will further elucidate our hypothesis by studying JNK, caspase 3 and 9 activity and downstream of both intrinsic, extrinsic apoptosis pathway. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-02-01.