Combined Treatment Strategies for Microtubule Interfering Agent-Resistant Tumors

Treatment resistances to specific anticancer agents and radiotherapy are often linked to the mutated genetic background of tumor cells. Their activities towards co-targeted tumor microenvironment-related cells are thereby also abrogated but could be reestablished as part of rationally-designed combined treatment modalities. Here we mechanistically investigate in two clinically relevant microtubule-interfering agent (MIA)-refractory tumor models the potency of combined treatment modalities of MIAs, inhibitors of angiogenesis and ionizing radiation to overcome MIA-resistance.

Single and combined treatment regimens of ionizing radiation, microtubule stabilizing (taxol, patupilone) and de-stabilizing (BAL101553) agents and anti-angiogenic compounds (everolimus, bevacizumab) were investigated in genetically defined MIA-sensitive and MIA-resistant lung and colon adenocarcinoma carcinoma cell systems (A549, SW480) and in the corresponding tumor xenografts.

MIAs potently inhibited A549wt and endothelial cell proliferation, while no anti-proliferative effect was observed in the corresponding MIA-resistant tumor cells. More important, MIAs did not downregulate anymore HIF-1alpha transcriptional activity and subsequent secretion of HIF-1alpha-mediated growth factors and cytokines from these MIA-resistant tumor cells. Continuous pro-survival auto- and paracrine signaling from these resistant tumor cells resulted in an additional level of treatment resistance towards MIAs and ionizing radiation as determined in tumor xenografts derived from MIA-resistant tumor cells. However rationally-designed combined treatment of MIAs with mTOR-signaling- or VEGF-antagonists strongly re-sensitized treatment-resistant tumors to the corresponding MIA.

These data demonstrate that the interaction between the tumor cell compartment and the tumor microenvironment strongly determines the treatment response to different anticancer treatment modalities. A combined treatment modality of MIAs with antiangiogenic agents is potent to overcome tumor cell-linked MIA-resistance and should be considered as clinical strategy for MIA-refractory tumor entities.