PDK1 Inhibition and Resistance to Cetuximab in Head/Neck Squamous Cell Carcinoma
Posted: Tuesday, December 24, 2019
A combination of PDK1 knockdown or inhibition by dichloroacetic acid with ASCT2 knockdown or with cetuximab therapy led to ROS overproduction and apoptosis in head and neck squamous cell carcinoma cells, according to study results published in the Journal of Clinical Investigation Insight. Zhen Fan, MD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues suggest additional clinical trials of the combination are warranted.
“This combination strategy is compelling for two main reasons,” the authors commented. “First, unlike previously proposed strategies to overcome cetuximab resistance, our strategy does not require functional inhibition of EGFR downstream cell signaling pathways by cetuximab in order to be effective…. Second, the combination of cetuximab with [dichloroacetic acid] not only induces cell death, but more importantly can induce cell death selectively in cancer cells.”
Looking at a total of 522 head and neck squamous cell carcinoma cells from The Cancer Genome Atlas and 44 normal tissues, among several other methods, the authors sought to understand whether the combination would be viable. Samples and materials were collected from centers internationally. For example, the HN5 cell lines were provided by Helmout Modjtahedi (Kingston University London), and Swiss nude mice were obtained from MD Anderson. Intracellular ROS was detected.
Although N-acetyl cysteine or glutathione were present, the ability of cetuximab to improve PDK1-targeted therapy was not as strong. Considering this finding, the study authors concluded that ROS appears to fulfill a role in the induction of apoptosis when combining cetuximab with PDK1 inhibition.
Disclosure: The study authors reported no conflicts of interest.