Ricerc@Sapienza

Colorectal cancer (CRC) is among the most frequent malignant diseases in Western industrialized countries, and one of the most common cancer types, accounting for 8.5% of cancer-related mortality [1]. Over the last ten years, the introduction of targeted agents in clinical practice has led to improvements in treatment of metastatic colon cancer. Among these, cetuximab is a partially humanized monoclonal antibody, raised against the epidermal growth factor receptor (EGFR), which abrogates EGFR signaling by impairing receptor dimerization, promoting receptor internalization and degradation, and by activating antibody-dependent cellular cytotoxicity [2]. Although the targeting of EGFR pathways has been quite successful, mutations in KRAS carry a negative response predictive value of 99%, making it an ideal predictive biomarker for EGFR targeted therapy [3]. This dramatically reduces the therapeutic options for advanced colorectal cancer harbouring KRAS mutations. Patients with RAS-mutant metastatic CRC (mCRC) have fewer treatment options available as compared to their RAS wild-type counterparts. Since current guidelines indicate that mCRC patients with RAS mutations should not be considered eligible for anti-EGFR therapy, in this group of patients¿ international guidelines recommend treatment with bevacizumab in first line, followed by a chemotherapy backbone change or aflibercept/ramucirumab at disease progression. Unfortunately, prognosis in RAS mutant CRC patients remains poor [4]. Therefore, identification of novel approaches to tackle cetuximab resistance would be key to sensitize cells to this therapy. There is an unmet clinical need for targeting KRAS-mutant tumors to circumvent therapeutic resistance, and a variety of rational combination strategies have been explored [5]. Essential oils have been shown to possess cancer cell targeting activity and are able to increase the efficacy of commonly used chemotherapy drugs including paclitaxel and docetaxel, having also shown proimmune functions when administered to the cancer patients [6]. Nevertheless, few data are available to date concerning the potential of essential oils to improve the efficacy of targeted agents. Recent evidence has been provided that terpinen-4-ol restores the sensitivity of KRAS mutant colorectal cancer cells to cetuximab, although the mechanism behind this phenomenon has not been clarified yet. Although the promoter activity was significantly reduced upon exposure to terpinen-4-ol, this observation needs to be further confirmed before leading to any clinical use of terpinen-4-ol [7].
The present proposal, which is aimed to elucidate the pathways affected by terpinen-4-ol in RAS mutant colon cancer cell lines might provide a rationale to improve the efficacy of EGFR-targeted therapy in KRAS-mutant tumors and to optimize the use of this compound in combination therapy. Although this is a relatively new and emerging area of cancer research, the analysis of cancer pathways affected by these natural compounds is compelling.
We hope these results would provide a starting point for clinical studies with terpinen-4-ol in patients with metastatic KRAS mutant CRC in combination with standard chemotherapy plus molecular targeting agents in order to improve clinical benefit for this difficult to treat patient population.
References
1. Dekker E et al. doi: 10.1016/S0140-6736(19)32319-0.
2. Fornasier G et al. doi: 10.1007/s12325-018-0791-0
3. Stahler A et al. doi: 10.1007/s00432-020-03290
4. Dienstmann R et al.doi: 10.1053/j.gastro.2019.12.051.
5. Gerber DE et al doi: 10.1007/s10555-010-9215-6
6. Blowman k et al. doi: 10.1155/2018/3149362
7. Shapira S et al.doi: 10.1371/journal.pone.0156540