Metabolic adaption of tumour cells is necessary to meet biosynthesis and energy needs of a growing cancer. The energy sensing kinase AMPK is responsible for maintaining AMP/ATP ratio, serving as a metabolic checkpoint that is activated when phosphorylated by the LKB1, a tumour suppressor kinase. LKB1 is frequently found mutated in numerous cancers including 31% of HER2 breast cancer.
Previously we generated a spontaneous mouse model of breast cancer that lacked LKB1 expression and was active for ErbB2. In our LKB1-/-NIC model, loss of LKB1 expression resulted in reduced tumour latency where tumours were biochemically characterized as hyperactive mTOR, along with metabolic changes characteristic of Warburg effect, namely elevated ATP, LDH, PDH expression and enhanced lactate. Based on these finding, we conducted a pre-clinical study to evaluate novel combinatorial therapies on tumourigenesis. To monitor tumour growth, MRI allowed for longitudinal sequential volumetric imaging.
We report that targeting PI3K-p70S6K pathways with competitive NVP-BEZ235 inhibitor was not as effective at reducing tumourigenesis as targeting mTOR and glycolysis with AZD8055 and 2-DG monotherapies, respectively. Interestingly, simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing mitochondria function, tumour volume and burden, culminating in reduced tumourigenesis. At the molecular level, combination treatment inhibited both mTOR signalling and blocked MAPK survival signalling that is responsible for ERK-p90RSK pathway engagement. Finally, loss of LKB1 expression in cancers should be considered a marker for metabolic dysfunction given the role LKB1 plays in regulating both AMPK activity and mTOR function.
The results of our pre-clinical study suggest that combinatorial therapy that target mTORC1/mTORC2 and glycolytic pathways in cancer, is critical for inhibiting tumour growth. Specifically, the combination therapies that target these pathways are likely to produce the best outcome in the treatment of patients harbouring HER2 breast cancers that are metabolically active.