Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond

Abstract

Colorectal cancer (CRC) is the third most diagnosed malignancy and a major leading cause of cancer-related deaths worldwide. Despite advances in therapeutic regimens, the number of patients presenting with metastatic CRC (mCRC) is increasing due to resistance to therapy, conferred by a small population of cancer cells, known as cancer stem cells. Targeted therapies have been highly successful in prolonging the overall survival of patients with mCRC. Agents are being developed to target key molecules involved in drug-resistance and metastasis of CRC, and these include vascular endothelial growth factor, epidermal growth factor receptor, human epidermal growth factor receptor-2, mitogen-activated extracellular signal-regulated kinase, in addition to immune checkpoints. Currently, there are several ongoing clinical trials of newly developed targeted agents, which have shown considerable clinical efficacy and have improved the prognosis of patients who do not benefit from conventional chemotherapy. In this review, we highlight recent developments in the use of existing and novel targeted agents against drug-resistant CRC and mCRC. Furthermore, we discuss limitations and challenges associated with targeted therapy and strategies to combat intrinsic and acquired resistance to these therapies, in addition to the importance of implementing better preclinical models and the application of personalized therapy based on predictive biomarkers for treatment selection.

Differential expression of angiogenesis-related genes ‘VEGF’ and ‘angiopoietin-1’ in metastatic and EMAST-positive colorectal cancer patients

“…Vascular endothelial growth factor (VEGF) is secreted by multiple cell types, including cancer cells, and plays a major role in endothelial cell survival, growth, differentiation, and migration. As previously reported, VEGF-expressing CRCs possess increased growth and metastatic potential compared to tumors with baseline VEGF expression 51 . In a cohort of 103 patients with mCRC, a high serum VEGF-A level was demonstrated as a valuable predictive biomarker of liver and lung metastasis 54 .…”

“…However, it is widely accepted that angiopoietins alone have limited potency, and they take part in the regulation of other angiogenic factors as well 50 . Like ANGPT-2, serum VEGF-A levels have been associated with the disease stage in CRC, with higher values being related to more advanced disease 51 – 53 . Vascular endothelial growth factor (VEGF) is secreted by multiple cell types, including cancer cells, and plays a major role in endothelial cell survival, growth, differentiation, and migration.…”

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance

“…PDX of colorectal cancer had HER2 activating mutations that were responsive to two TKIs, EGFR/HER2 Neratinib and Afatinib, and that resulted in tumor regression when coupled with TKIs and Trastuzumab. The oncogenesis of colon epithelial cells has also been linked to these mutations and resistance to anti‐EGFR monotherapy 66,67 …”

“…The oncogenesis of colon epithelial cells has also been linked to these mutations and resistance to anti-EGFR monotherapy. 66,67 Several clinical trials have validated the preclinical research findings that address HER2 alterations in conjunction with chemotherapy treatments in patients with metastatic colorectal cancer. Due to excessive toxicity and poor accrual, earlier clinical trials examining the combination of Cetuximab or chemotherapy with HER2 mAbs (Epratuzumab or Trastuzumab) were discontinued.…”

Optimizing the first-line treatment for metastatic colorectal cancer

“…The identification of mutations in progress could potentially anticipate disease progression and suggest the combination of target treatments in selected patients. There are several studies, involving different molecules and different oncological pathologies, which are trying to validate an algorithm applicable in clinical practice ( 2 ). Considering that MSS and MSI-H mCRC tumors are two different entities of the same disease that differ both in etiologic, clinical, pathological and treatment outcome characteristics, the first step is to divide the stable disease from the unstable one.…”