Page 64 - D. Cancer biology

[D. Cancer biology-46]

Differential sensitivity of BRAF- and RAS-mutated cells to

autophagy inhibition

Hojin Yeom¹, Sung-Hee Hwang¹, Byeal-I Han², Michael Lee¹˙²˙*

¹Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon

22012, Republic of Korea, ²Institute for New Drug Development, Incheon National University, Incheon 22012,
Republic of Korea

The deregulation of autophagy is frequent in malignancy. In this study, we investigated the therapeutic effects of

autophagy inhibition on tumor cells containing BRAF-mutations. All the BRAF mutant cells were highly sensitive to

PLX4720 compared to cells with WT BRAF. We observed the increased basal autophagic flux in BRAF-mutated cells
compared with WT BRAF cells as determined by LC3 conversion and immunofluorescence using the tandem probe
RFP-GFP-LC3. Combination treatment with PLX4720 and early autophagy inhibitor SBI-0206965 resulted in

significantly greater cytotoxicity than each inhibitor alone regardless of BRAF mutation. However, late autophagy
inhibitor hydroxychloroquine did not show synergistic effect in combination with PLX4720. We also observed

synergistic anti-survival effects of MEK inhibitor trametinib when combined with PLX4720 in SK-MEL-2 cells but not
in A375P cells. Taken together, our results suggest that while combined inhibition of early autophagy with BRAF

inhibitor might be a therapeutic strategy for BRAF mutant cells, targeted therapies that inhibit MEK signaling may
prove a more effective treatment strategy for BRAF WT cells. (Supported by the National Research Foundation of

Korea grant funded by the Ministry of Science and ICT (NRF-2019R1F1A1048733)).