Cetuximab is a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR), competing with endogenous ligands for binding to receptor extracellular domain, thereby inhibiting activation of tyrosin kinase (TK). However, RAS mutations contribute to the resistance through constitutive activation of EGFR downstream signaling cascades regardless of EGFR blockade, leading, as a result, to the approval of the antibody for clinical use in only wild-type metastatic colorectal cancer patients. Consequently, it is reasonable to believe that modulation or inhibition of the resistance pathways might be an effective way to restore sensitivity to EGFR inhibition. The need to identify a strategy that might sensitize tumor cells to therapeutic agents has led the cancer research community to a continuous search for effective chemosensitizers overcoming resistance. The identification of naturally occurring substances displaying action against cancer is one of the supreme domains of current day research. At this regard, it was shown that essential oils possess cancer cell targeting activity and are able to enhance the efficacy of commonly used chemotherapy drugs selectively in tumor cells, limiting any undesired toxicity or side effects in normal cells. It is particularly worthy of mention that cinnamon essential oil, as a whole and/or its components, exhibits significant anticancer activity through the inhibition of EGFR-TK and is able to restore the sensitivity to EGFR antagonists in tumors with RAS mutations. Therefore, it would be interesting to investigate whether cinnamon essential oil, a multitargeting compound, in combination with cetuximab could sensitize mutant RAS colorectal cancer cells, thus increasing the EGFR-inhibitor efficacy.
To date, colorectal cancer (CRC) harboring KRAS mutations are judged as ineligible for anti-EGFR targeted therapies and are doomed to rely on the inhibition of angiogenesis as the only actionable molecular target. Primary resistant tumors, harboring KRAS mutations, appear to be neglected by researchers and the importance of the EGFR pathway, which indeed sustains the disease, is ignored as potential therapeutic target. Recommendations for medical oncologists take no notice of the molecular background of a priori resistant mutant KRAS CRC and ignore potential strategies to inhibit the addiction of cancer clones to the EGFR pathway. The proposed in vitro experiments will eventually provide evidence on the possibility that cinnamon essential oils might restore sensitivity to EGFR-inhibitors, thus increasing, at least in a certain proportion of patients, the therapeutic chances.