Tuesday, May 13, 2014

KRAS Mutations Drive Acquired Resistance to Cetuximab in Colorectal Cancers?

          For the cancer project, Ramez Sakkab and I are taking a closer look at colorectal cancer (CRC) therapy. A popular type of therapy is anti-EGFR therapy, targeting the epidermal growth factor receptor (EGFR).  EGFR is a receptor tyrosine kinase that activates KRAS, which eventually leads to the expression of growth-promoting genes. EGFR also activates another pathway that results in protein synthesis, cell growth, survival, and proliferation. The inhibition of EGFR is beneficial for CRC patients, but after an initial response to therapy, some grow to be resistant. The paper that I am interested in investigates this resistance specifically to the drug cetuximab, which binds the extracellular domain of EGFR, preventing ligand binding and interrupting the signal cascade. The authors conclude that mutations of KRAS have a causal relationship with the acquired resistance to anti-EGFR treatment. For this first blog post, I will address my initial thoughts and impressions regarding this paper.

          Without yet delving into the data presented, I already questioned the strength of this paper’s claim. A causal relationship is a heavy assertion, and the tests and trials must be well conducted. A casual conclusion brings to mind an interventional trial, ideally a randomized control trial, but in the context of what is being studied, the researchers studied patients already suitable for the case instead, the ones who have acquired resistance to cetuximab. Only 21 patients were used in the study, possibly questioning the credibility of the conclusion.

          In addition, the authors state in the abstract that 60% of cases with patients who grew resistance had secondary KRAS mutations. What about the other 40% of patients? If their resistance was not caused by a KRAS mutation, could that same reason also be affecting the other 60%? This leads to my next thought, which would be how the researchers eliminated other proteins in the signaling pathway related to EGFR, or other factors, and found KRAS to be the culprit. Also, the molecular basis for the acquired resistance remains unknown, adding to the pressure of the accuracy of the clinical trials.

           For my next blog post, I will dive deeper into this paper and look closely at the study’s data sets to reevaluate my initial concerns.

Sandra Misale, Rona Yaeger, Sebastijan Hobor, Elisa Scala, Manickam Janakiraman, David Liska, Emanuele Valtorta, Roberta Schiavo, Michela Buscarino, Giulia Siravegna, Katia Bencardino, Andrea Cercek, Chin-Tung Chen, Silvio Veronese, Carlo Zanon, Andrea Sartore-Bianchi, Marcello Gambacorta, Margherita Gallicchio, Efsevia Vakiani, Valentina Boscaro, Enzo Medico, Martin Weiser, Salvatore Siena, Federica Di Nicolantonio, David Solit, and Alberto Bardelli. “Emergence of KRAS mutations and acquired resistance to anti EGFR therapy in colorectal cancer.” Nature (2012) 486:7404. Web May 3, 2014.