Resistance in PaCSCs

Although resistance can develop in PaCSCs in response to treatment with OXPHOS inhibitors, it can be combated through the inhibition of the protein Myc. PaCSCs’ dependence on OXPHOS is mediated by Peroxisome proliferator-activated receptor γ co-activator 1 α (PGC-1α), a transcription factor that is inversely regulated by the expression of the c-Myc oncogene. The Myc protein is expressed at low to undetectable levels in PaCSCs normally, thus indicating a high expression of PGC-1α (Sancho et al. 2015). When resistance in PaCSCs arises, c-Myc expression increases as well. This resistance has been reversed with inhibition of c-Myc (Sancho et al. 2015). Therefore, the researchers will include a c-Myc inhibitor in all phases of treatment to continually combat this resistance. RRx-001 is a minimally toxic c-Myc inhibitor that has been found to effectively target CD133+/CD44+ cancer stem cells from colon cancer (Oronsky et al. 2018). It also inhibits Wnt signaling as a result of this c-Myc downregulation. The researchers plan to incorporate RRx-001 into their treatment to further suppress PaCSC self-renewal and resistance.