A Perspective on Therapeutic Pan-Resistance in Metastatic Cancer

Abstract

Metastatic spread represents the leading cause of disease-related mortality among cancer patients. Many cancer patients suffer from metastatic relapse years or even decades after radical surgery for the primary tumor. This clinical phenomenon is explained by the early dissemination of cancer cells followed by a long period of dormancy. Although dormancy could be viewed as a window of opportunity for therapeutic interventions, dormant disseminated cancer cells and micrometastases, as well as emergent outgrowing macrometastases, exhibit a generalized, innate resistance to chemotherapy and even immunotherapy. This therapeutic pan-resistance, on top of other adaptive responses to targeted agents such as acquired mutations and lineage plasticity, underpins the current difficulties in eradicating cancer. In the present review, we attempt to provide a framework to understand the underlying biology of this major issue.

Keywords: disseminated tumor cells; dormancy; e-cadherin; epigenetics; immune checkpoint blockade; metabolic plasticity; metastasis; metastatic microenvironment; therapy resistance.

Figure 1

E-cadherin mediates micrometastatic dormancy and chemoresistance. Hepatocytes induce E-cadherin upregulation in metastatic prostate cancer as well as other epithelial markers, thus promoting a partial cancer-associated mesenchymal-to-epithelial reverting transition (cMErT) by initial suppression of p38 and ERK. Upon cell-cell E-cadherin ligandation, stimulation of metastatic cells with chemotherapy induces activation of canonical pro-survival kinases resulting in increased chemoresistance. This chemoresistance is proliferation-independent and can be targeted with an adjuvant treatment to achieve optimal efficacy with traditional chemotherapies. DTCs: disseminated tumor cells.

Figure 2

Metastatic microenvironment dictates emergence from dormancy and treatment resistance. Reawakening of disseminated tumor cells (DTCs) from dormancy may be triggered by changes in the microenvironment in which these DTCs reside or even changes in immune activity. Key signaling components involved in metastatic reactivation include collagen, laminin, and fibronectin interacting with integrins and DDR (Discoidin Domain Receptor). Neutrophils recruited can produce neutrophil extracellular traps (NETs) and the associated proteases permit the integrin-mediated activation of dormant DTCs that proliferate to form macrometastases. Concurrently, binding of tumor cells to these ECM components trigger inhibition of drug-induced apoptosis and resistance to targeted therapies. Tonic activation of EGFR by tenascin C also provides survival signaling. Finally, the density of the matrix impedes the diffusion of chemotherapy agents.

Figure 3

Roles of immune system in DTC dormancy and reawakening. This simplified schematic diagram shows that dormant DTCs may upregulate unfolded protein response (UPR) activity, which results in MHC-I downregulation and thus impaired immunological visibility to NK cells and CD8+ (cytotoxic) T cells. Downregulation of PD-L1 is a potential mechanism through which dormant DTCs may evade immunotherapy based on PD-1/PD-L1-blockade. Emergence of outgrowing metastases is linked to the activities of several immune cells, including regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and metastasis-associated macrophages (MAMs), and also upregulation of immune markers such as PD-L1.