The TRAIL to targeted therapy of breast cancer

Abstract

Breast cancers can be classified into those which express the estrogen (ER) and progesterone (PR) receptors, those with HER-2 amplification, and those without expression of ER, PR, or amplified HER-2 (referred to as triple-negative or basal-like breast cancer). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates apoptosis upon binding to its receptors in many tumor types and the ligand and agonist antibodies are currently being studied in patients in clinical phases I and II trials. Cell line studies suggest that many breast cancer cell lines are very resistant to TRAIL-induced apoptosis. However, recent data suggest that a subset of triple-negative/basal-like breast cancer cells is sensitive to TRAIL as a single agent. In addition, many studies have demonstrated that resistance to TRAIL-mediated apoptosis in breast cancer cells can be overcome by combinations of TRAIL with chemotherapy, radiation, and various targeted agents. This chapter will discuss the current understanding of the mechanisms, which control TRAIL-mediated apoptosis in breast cancer cells. The preclinical data supporting the use of TRAIL ligands and agonistic antibodies alone and in combination in breast cancer will also be discussed.

Fig. 1

Apoptosis pathways. Different stimuli and cell stresses result in activation of distinct initiator caspases (i.e., caspases 2, 8, 9, 10, and 12 shown in gray boxes) as discussed in the text. These in turn cleave and activate down stream effector caspases (e.g., caspases 3, 6 and 7). The primary initiator caspase can activate secondary initiator caspases as discussed in text (dashed arrows). The activation of effector caspases leads to apoptotic cell death.

Fig. 2

Death receptor pathway. TNF family death ligands (e.g., TNF, FAS, TRAIL) bind to their cognate receptors and initiate the formation of the death inducing signaling complex (DISC). All of the TNF family receptors which induce apoptosis contain a highly conserved death domain (DD) in their cytoplasmic tails. The adaptor protein FADD contains an N-terminal death effector domain (DED) and a C-terminal DD. FADD is recruited to the activated receptor by homotypic interations between the C-terminal DD of FADD and the DD of the receptor. Inactive caspase 8 and caspase 10 zymogens are recruited to the DISC by homotypic interactions between the N-terminal DED domains of the caspases and FADD. cFLIP can be recruited to the DISC and prevents recruitment of caspase 8 or 10. The recruitment of caspase 8 or caspase 10 to the DISC results in activation of the caspases and auto-processing into the active forms of the caspase (reviewed in Riedl and Shi, 2004). Activated caspase 8 or caspase 10 can directly activate effector caspases (e.g., caspases 3, 6, and 7). Activated caspase 8 or caspase 10 also can cleave the BH3 only protein Bid. Cleaved Bid (tBid) translocates to the mitochondria where it activates the extrinsic pathway.

Fig. 3

TRAIL receptors. TRAIL-R1 and TRAIL-R2 are type I transmembrane proteins that contain a DD. Ligand binding to these receptors results in activation of caspases. TRAIL-R3 is a glycophospholid-anchored cell surface protein, TRAIL-R4 is a transmembrane protein lacking an intact DD, and TRAIL-R5 is a secreted protein. These proteins bind TRAIL but are unable to activate caspases. These receptors act as decoy receptors and can inhibit TRAIL-mediated apoptosis by competing with TRAIL-R1 and TRAIL-R2 for the ligand.

Fig. 4

TRAIL agonists. Clinical trials testing TRAIL (a.k.a. rhApo2L), an agonistic TRAIL-R1 antibody (mapatumumab), and agonistic TRAIL-R2 antibodies (lexatumumab and apomab) are currently ongoing.

Fig. 5

TRAIL selectively kills mesenchymal triple-negative breast cancer cell lines. (Top) Growth inhibition of breast cancer cells incubated with TRAIL. Black lines represent mesenchymal triple-negative cell lines, green lines represent epithelial triple-negative cell lines; blue lines represent HER-2 amplified cell lines, and red lines represent ER positive cell lines. (Bottom) Characterization of ER and HER-2 expression in the breast cell lines. This figure is reproduced with kind permission of Springer Science and Business Media from Fig. 1 in (Rahman et al., 2009).

Fig. 6

Cell surface expression of TRAIL-R1 and TRAIL-R2 do not correlate with TRAIL-senstivity. Mean cell surface expression of TRAIL-R1 and TRAIL-R2 in seven TRAIL-sensitive and seven TRAIL-resistant breast cancer cells was measured by flow cytometry (see text for discussion).