Drug resistance and new therapies in colorectal cancer

Abstract

Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.

Keywords: Colorectal cancer, Therapy resistance, Antibody-drug conjugates, α-amanitin, Tumor microenvironment, Immunotherapy, Checkpoint inhibitors, Microbiome

Core tip: Therapy resistance has been a culprit for colorectal cancer (CRC) treatment. Here, we review a novel therapeutic approach using α-amanitin antibody-drug conjugates inhibiting RNA polymerase II against CRC with hemizygous loss of p53. Since its mechanism of cell killing is independent of the generally used tubulin inhibitors and chemotherapy drugs, this approach shows the promise to overcome common drug resistance. In addition, we summarize the sensitivity of CRC to newly developed immune checkpoint inhibitors. While patients with microsatellite instability-high CRC remain the sole subgroup responsive to current checkpoint inhibitors so far, we highlight potentially new developments that may lead to promising results in treating patients with microsatellite-stable CRC, which constitutes the majority of this disease.