In the Brown laboratory, we investigate mechanisms that drive resistance to chemotherapy and targeted therapy agents in breast cancer.
This knowledge is applied to the pre-clinical development of novel and more effective interventions for breast cancer therapy.
Metabolic reprogramming and chemotherapy resistance in triple-negative breast cancer
Triple-negative breast cancer (TNBC) is a subtype of breast cancer for which treatment options are limited to conventional chemotherapy agents. Chemotherapy resistance is a major barrier to the successful treatment of TNBC, and there is a critical need to identify novel and actionable strategies to circumvent resistance and enhance the efficacy of chemotherapy. Using an unbiased metabolomics platform, we have identified the spectrum of metabolic reprogramming events induced when TNBC cells are exposed to clinically relevant chemotherapy agents, and identified metabolic pathways that act as critical nodes of regulation by chemotherapy.
Using a variety of in vitro and in vivo techniques, we seek to:
- Thoroughly characterise the contribution of the identified metabolic pathways to chemotherapy resistance and breast cancer progression.
- Identify novel therapeutic approaches to exploit these adaptive metabolic reprogramming events and sensitise TNBCs to chemotherapy.
Effectors of oncogenic SGK1 signalling in breast cancer
The phosphoinositide 3-kinase (PI3K) pathway is a master regulator of processes that contribute to tumour development and maintenance. Deregulation of the PI3K pathway is implicated in virtually all cancers and as a consequence the pathway has been aggressively targeted for cancer therapy. Although most work has focused on the Akt kinase family as major downstream effectors of PI3K, the closely related serum and glucocorticoid-regulated kinase (SGK) family (comprising SGK1, SGK2 and SGK3) has by comparison received little attention. SGK1 plays a critical role in driving the expansion of tumour cells and can promote resistance to both conventional chemotherapy and targeted therapy agents. However, the mechanisms that permit SGK1 to elicit its oncogenic activities are largely unknown.
We seek to identify SGK1 substrates and interacting proteins, and to investigate the contribution of these downstream effectors to breast cancer progression and therapy resistance. These studies will identify novel targets for therapeutic intervention.
Brown KK*, Spinelli JB, Asara JM, Toker A* (2017). Adaptive reprogramming of de novo pyrimidine synthesis is a metabolic vulnerability in triple-negative breast cancer. Cancer Discov. 7(4):391-9. *Co-corresponding authors
Cox AG, Hwang KL, Brown KK, Evason KJ, Beltz S, Tsomides A, O'Connor K, Galli GG, Yimlamai D, Chhangawala S, Yuan M, Lien EC, Wucherpfennig J, Nissim S, Minami A, Cohen DE, Camargo FD, Asara JM, Houvras Y, Stainier DY, Goessling W (2016). Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat Cell Biol. 18(8):886-96.
Brown KK, Montaser-Kouhsari L, Beck AH, Toker A (2015). MERIT40 Is an Akt substrate that promotes resolution of DNA damage induced by chemotherapy. Cell Rep. 11(9):1358-66.
Brown KK, Toker A (2015). The phosphoinositide 3-kinase pathway and therapy resistance in cancer. F1000Prime Rep. 7:13.
Banerji S*, Cibulskis K*, Rangel-Escareno C*, Brown KK*, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, Sougnez C, Zou L, Cortes ML, Fernandez-Lopez JC, Peng S, Ardlie KG, Auclair D, Bautista-Piña V, Duke F, Francis J, Jung J, Maffuz-Aziz A, Onofrio RC, Parkin M, Pho NH, Quintanar-Jurado V, Ramos AH, Rebollar-Vega R, Rodriguez-Cuevas S, Romero-Cordoba SL, Schumacher SE, Stransky N, Thompson KM, Uribe-Figueroa L, Baselga J, Beroukhim R, Polyak K, Sgroi DC, Richardson AL, Jimenez-Sanchez G, Lander ES, Gabriel SB, Garraway LA, Golub TR, Melendez-Zajgla J, Toker A, Getz G, Hidalgo-Miranda A, Meyerson M (2012). Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 486(7403):405-9. (* Equal first authors)
Christoforides C, Rainero E, Brown KK, Norman JC, Toker A (2012). PKD controls αvβ3 integrin recycling and tumor cell invasive migration through its substrate Rabaptin-5. Dev Cell. 23(3):560-72.