Functional Consequences And Clinical Significance Of Tyrosine Kinase Inhibitors In Advanced Colorectal Cancer

Keywords

Colorectal cancer; EGFR; Tyrosine kinase inhibitors; VEGF

Abstract

Colorectal cancer (CRC) is an important public health issue as the 5-year prognosis is <20% for newly diagnosed metastatic CRC (mCRC). In recent years, screening modalities have led to early detection of the disease, which has shown some promise for improved survival. The advancements in adjunctive treatments and aggressive surgical treatment are also partly responsible for this success, but the deeper understanding of carcinogenesis and targeted molecular therapy has made a stronger impact with the emergence of newer targets in the recent past. Particularly, the development and FDA approval of newer drugs, including capecitabine, irinotecan, oxaliplatin, monoclonal antibodies that block either VEGF (bevacizumab, aflibercept, and ramucirumab) or the EGFR (cetuximab and panitumumab), and most recently, trifluridine/tipiracil and regorafenib (TAS-102), have been remarkable in this area of research. The clinical benefits of these drugs are now generally acceptable/established for mCRC patients, with the median overall survival of >30 months. Currently, limitation in the effectiveness of tyrosine kinase inhibitors (TKIs) is due to (i) combination chemotherapy use that necessitates lowering of the dose density for toxicity profile management, and (ii) these drugs have mainly been developed in molecularly unselected population. The main challenge now is the identification of more reliable and 116 specific predictive biomarkers for selecting the most suitable therapy for mCRC. So far, the only well-established/reliable biomarker for mCRC treatment is RAS mutational status, which predicts negative response to anti-EGFR therapy. Current recommendation for the BRAF mutational status has also been given by the NCCN and the ESMO. Unlike VEGF inhibitor therapy, the resistance mechanisms in the EGFR inhibitor therapy are well understood, as are the drugs blocking the downstream RAS-MAPK pathway. Notably, a number of clinical trials on targeting the RAS signaling pathway have revealed promising efficacy in chemo-refractory mCRC. This chapter discusses the role of TKIs in advanced CRC from both translational and clinical research points of view.

Publication Date

1-1-2018

Publication Title

Role of Tyrosine Kinases in Gastrointestinal Malignancies

Number of Pages

115-140

Document Type

Article; Book Chapter

Personal Identifier

scopus

DOI Link

https://doi.org/10.1007/978-981-13-1486-5_10

Socpus ID

85063460704 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85063460704

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