Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment

Abstract

The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).

Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review

“…As illustrated in Figure 1B, the collision of the DNA replication fork, together with this ternary complex formation, ultimately results in lethal and irreversible double-strand breaks [4] . Individual differences in metabolic capacities should thus be considered for individualized irinotecan therapy [5] . The mechanism of the anti-cancer activity of SN-38 is the stabilization of the DNA Top1-DNA cleavable complex in cancer cells, resulting in the arrest of DNA replication [2] .…”

“…Even though various human cancers are treated with irinotecan, refractoriness remains a significant problem, as is the case with most other anti-cancer drugs. With regard to drug therapy for colorectal cancer (CRC), cellular and molecular mechanisms of failure in irinotecan therapy seem to be roughly classified into the following six categories: (1) drug uptake and export; (2) drug metabolism; (3) changes in drug targets; (4) phenotype transition; (5) adaptation to the tumor microenvironment; and (6) colon cancer stem cells (CSCs) [6] .…”

Targeting of TP53-independent cell cycle checkpoints overcomes FOLFOX resistance in Metastatic Colorectal Cancer

“…This study aimed to identify mechanisms of resistance to FOLFOX, the most frequently prescribed regimen in patients with stage II and IV CRC 13 . While various mechanisms have been identified for oxaliplatin or 5-FU monotherapy (including proteins involved in drug uptake, export and metabolism, modulation of thymidylate synthase expression, or alterations of apoptosis/survival effectors, as reviewed), there are few preclinical studies investigating resistance to 5-FU/Oxaliplatin combinations 37 . Among those, previous studies have suggested that ERCC1 over-expression, leading to increased DNA damage repair through the nucleotide excision repair pathway, correlates with FOLFOX resistance 38,39 .…”

Identifying Novel Actionable Targets in Colon Cancer

“…Notably, the miR-34a mimic MRX34 is the first synthetic miRNA entered into clinical trials (for an extensive review on the topic, see [36]). Other mechanisms of resistance to 5-FU, and chemotherapy in general, have been reported, such as altered expression of drug uptake carriers and efflux pumps, changes in phase I and phase II enzymes involved in drug metabolism (resulting in decreased pharmacological action either by an enhanced generation of inactive metabolites or diminished activation of prodrugs), altered expression levels of drug targets (such as thymidylate synthase, the target of 5-FU), enhanced capacity of tumor cells to repair the DNA damage usually induced by chemotherapeutic drugs or, to the contrary, dysfunction of the DNA damage sensing machinery and inability to undergo cell death after exposure to DNA damaging chemotherapy (such as upon TP53 loss) (for an extensive review on the topic, see [40]).…”