Unidad de Oncología Traslacional

Project title

Study of the role of cGMP signalling in primary resistance to cetuximab in KRAS Wild-Type metastatic colorectal cancer: a metabolic approach.

Metastatic colorectal cancer (mCRC) remains a challenge due to its low cure rate. The appearance of targeted anti-EGFR therapies in patients with native RAS mCRC has contributed substantially to prolonging their survival. However, disease control remains unsuccessful due to primary resistance, highlighting the necessity of discovering additional cetuximab-selective biomarkers. During the last years, the cyclic GMP signaling pathway has emerged as an important phenomenon in the differentiation of intestinal epithelium and its deregulation has been linked to oncogenic processes and metabolic changes that increase the aggressiveness of colorectal tumors. Since metabolic adaptation has been described as a resistance mechanism to anti-EGFR therapies, it would not be surprising that the loss of cGMP signaling could promote cetuximab resistance through changes in cell metabolism. In this project, the role of cGMP signaling in cetuximab resistance will be analyzed from a metabolic perspective. The objectives to be achieved by the student will be the following:

• Characterization of cGMP signaling status in CRC cell lines with known response status to anti-EGFR therapies.
• Define the metabolic profile of CRC cell lines with known response status to anti-EGFR therapies.
• Elucidate the effect of changes in cyclic GMP signaling on the response to cetuximab in CRC cell lines with silencing or overexpression of key genes of this signaling pathway.  
• Define the changes in cellular metabolism caused by alterations in cGMP signaling.
• Study of gene expression changes through RNA-Seq caused by the alteration of cyclic GMP signaling.
• Search for new therapeutic targets related to cGMP signaling and proposal of new combination therapies to reverse primary resistance to anti-EGFR therapies.

Student Profile

We are looking for highly motivated students, preferably with availability to start in November.