Congratulations to Dr Bhattacharya Bhaskar Umashanka on receiving the prestigious AACR-Aflac, Incorporated Scholar-In-Training Award from the American Association for Cancer Research. His paper was chosen for the AACR Annual Meeting 2013 to be held in Washington this April, which aims to bring together the best and latest findings in cancer research.
Rated “outstanding” by the judging panel, Dr Bhaskar’s paper was selected from a highly competitive and rigorous selection process that awards just 1% of its applicants. Through this program, the AACR hopes to enhance the education and training of early-career scientists by supporting their attendance at AACR conferences and meetings.
Dr Bhaskar is a Research Fellow under A/Prof Richie Soong’s group at the Cancer Science Institute of Singapore.
Bhaskar Bhattacharya, Sarah Low, Meiqi Yee, King Xin Koh, Richie Soong. Cancer Science Institute of Singapore.
Title: Attenuation of hypoglycemia-associated resistance to PI103 and KU63794 through their synergistic combination in PIK3CA-mutant gastric cancer cells
Abstract: Drug testing in vitro has traditionally been performed in hyperglycemic culture conditions, yet many tumours and their microenvironments are hypoglycemic. Hypoglycemia could contribute to drug resistance through many mechanisms such as activation of stress and survival pathways, and by altering tumour bioenergetics. The aim of this study was to evaluate if hypoglycemia reduces drug sensitivity, and test strategies to attenuate any resistance. Two gastric cancer (GC) cells with PIK3CA mutations (AGS, HGC27) and two without (MKN45, NUGC4) were cultured in routine high glucose (HG) (25mM) or low glucose (LG) (5mM) DMEM. The IC50s of PI103 (PI3K/mTOR inhibitor), and KU63794 (mTOR inhibitor) were measured at 72h using MTS assay. Protein and cell cycle analysis were performed by ELISA and PI/RNase staining respectively. Combination analysis was performed using combination index (CI) method of Chou and Talalay. Cells with mutant (mt) but not wildtype (wt) PIK3CA displayed significant resistance to both PI103 and KU63794 in LG compared to HG conditions (Table 1), despite having similar doubling times and cell cycle profiles. Basal protein analysis revealed increased p-mTOR, p-S6, p-4EBP1 and GLUT1 in PIK3CA mt cells grown in LG compared to HG conditions. The levels of these proteins did not differ in PIK3CA wt cells, in addition to p-Akt in all cells. The activation of the mTOR pathway prompted the testing of the combination of PI103 and KU63794. The combination was synergistic in AGS and HGC27 cells (CI=0.09, p=0.012 and CI=0.13, p=0.032 respectively) in LG conditions, and additive in HG conditions. Furthermore, synergy was associated with significant reduction in p-4EBP1 and extracellular lactate concentration. No synergy was seen in the wt cell lines. These results suggest that hypoglycemia can reduce drug sensitivity, and that resistance to PI103 and KU63794 in hypoglycemic conditions can be circumvented by combining the two agents.