Abstract
The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as mono-therapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted.
Highlights
In the last fifteen years, the introduction of at least six key drugs, after the ‘‘era’’ of 5-fluorouracil as a single agent, has improved median overall survival of metastatic colorectal cancer patients up to 24 months [1,2]
We preliminary selected a panel of human CRC cells harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes
We observed that the effect elicited on cell viability by gabexate mesilate alone was similar to that observed when this drug was administered in combination with cetuximab 100 mg/ml (Figure 1)
Summary
In the last fifteen years, the introduction of at least six key drugs (oxaliplatin, irinotecan, capecitabine, bevacizumab, cetuximab and panitumumab), after the ‘‘era’’ of 5-fluorouracil as a single agent, has improved median overall survival of metastatic colorectal cancer (mCRC) patients up to 24 months [1,2]. In recent years, activating mutations at codons 12 and 13 in the KRAS oncogene (KRASG12V and KRASG13D) have emerged as the best predictive factors of low/absent response to anti-EGFR therapy in these patients, either in the first-line or subsequent lines of treatment [3,4,5]. For this reason, mCRC patients are profiled for KRAS mutation and the employment of cetuximab and panitumumab is currently restricted only to those ones bearing the KRAS wild-type, as recommended by the European Medical Agency and the American Society of Clinical Oncology [6]. Due to the lack of an effective targeted therapy, the discovery of new therapeutic options for mCRC patients with mutated KRAS, BRAF and PIK3CA genes represents an intense area of investigation
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