The events downstream of the death receptors can activate inflammatory signalling cascades and drive cell death. However, dysregulation of these signalling events is directly linked to one of the key h_a_l_l_m_a_r_k_s_ _o_f_ _c_a_n_c_e_r_,_ _‘e_v_a_s_i_o_n_ _o_f_ _a_p_o_p_t_o_s_i_s_’. Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a potent death-inducing cytokine which preferentially kills transformed cells. TRAIL receptor agonists, however, have performed poorly in the clinic due to major gaps in our understanding of what drives resistance to these potent death inducers. Thus, the proteins that can limit TRAIL receptor-mediated apoptosis are a major target for cancer therapy.
We have identified two new proteins; the E3 ubiquitin ligase Mind Bomb-2 (MIB2) and a novel MIB2 interacting protein that inhibit TRAIL receptor signalling. For the first time we have demonstrated that the removal of either of these proteins is sufficient to sensitise tumour cells to TRAIL-induced cell death.
Furthermore, we have e_m_p_l_o_y_e_d_ _a_n_ _i_n_n_o_v_a_t_i_v_e_ _‘p_r_o_o_f_ _o_f_ _p_r_i_n_c_i_p_l_e_’ _PROteolysis TArgeting Chimera (PROTAC) approach to trigger the degradation of these molecules by directing PROTACs towards small epitope tags (dTAG). PROTACs are small bi-functional compounds that simultaneously bind a target protein and an E3 ligase resulting in target degradation. dTAG technology has significant advantages over existing genetic approaches as it faithfully recapitulates real drug scenarios by allowing rapid and importantly reversible depletion of protein targets. Importantly, using dTAG technology we can now for the first time assess the therapeutic potential of targeting our two novel TRAIL signalling regulators for cancer treatment.