In my last blog post, I examined questionable factors of a paper whose authors conclude that KRAS mutations drive acquired resistance to an anti-EGFR therapy drug called cetuximab for colorectal cancers. My main concern is with the strength of the authors’ conclusion and if the data is sufficient enough to lead to a causal relationship. This paper presents two main overall sets of data. The first is in regards to the molecular mechanisms of secondary resistance to anti-EGFR therapies, while the second set attempts to determine clinically if KRAS mutations or amplifications are related to acquired cetuximab resistance. For this blog post, I will examine one part of the first data set.
The study was conducted with two colorectal cancer cellular models. One is called DiFi, the other Lim1215. Both lines were generated to be similar on a molecular level to the colorectal cancer patients who most likely would respond to cetuxtimab. DiFi cells overexpress EGFR due to the amplification of the EGFR gene. On the other hand, Lim1215 cells express normal levels of EGFR, while still being similarly sensitive to cetuximab as DiFi cells. From these two models, the researchers produced the cetuximab-resistant variants (DiFi-R, Lim1215-R), which are extremely sensitive to EGFR inhibition. One concern is that the methods section of the paper did not delve much into the specifics of how the cells were generated, so I am unsure how the cells function and how they are equally resistant to cetuximab.
This blog post will focus on the DiFi cells and their resistant lines.
My next post will look into the data of the other model, Lim1215.
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.