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.
References:
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.
