Oncogene Signaling

​Activation of proto-oncogenes results in alterations of multiple signaling pathways, resulting in the rewiring of cell proliferation, metabolism and small RNA circuits which contribute to the tumorigenic state.  Despite the discovery of numerous driver oncogenes in cancer, many of the most prevalent oncogenic alterations, such as activation of MYC or RAS cannot yet be readily blocked with small molecule inhibitors.  Our laboratory seeks to elucidate how oncogenes reprogram signaling to uncover new vulnerabilities in cancer cells.

Recently, our laboratory found that embryonic stem cells and MYC-driven tumors have an altered cell cycle program that renders then exquisitely sensitive to inhibition of the master cell cycle regulator CDK1. We have developed chemical-genetic tools, that for the first time, should allow us to precisely inhibit different cell cycle kinases and probe the effects in normal and tumor cells.

Our laboratory has identified how different oncogenes reprogram cellular metabolism.  For example, we found that MYC-driven breast tumors are critically dependent on fatty acid oxidation for their survival and proliferation.  We are currently exploring the molecular mechanisms that underlie the dependence of MYC and RAS-driven tumors on different metabolic pathways.

We seek to address several critical processes that oncogenes reprogram in tumorigenesis:

  • How do different oncogenes drive the cell cycle and does this result in unique vulnerabilities for oncogene transformed cells? ​

  • How is cellular metabolism reprogrammed by oncogenes, such as MYC and RAS, in primary tumors?
 
  • Does oncogene activation alter the repertoire of small RNAs expressed in transformed cells, and which of these are critically important for tumor growth?
 
  • What is the basis of tumor heterogeneity during the process of metastasis?  Can we identify unique vulnerabilities that will allow us to selectively target cancer metastasis?


Primary Thematic Area: Cancer Cell Biology & Cell Signaling

Secondary Thematic Area: Developmental & Stem Cell Biology

Research Summary:  Oncogene Signaling

Awards and Honors

​2011        American Society for Clinical Investigations
2012       CDMRP Era of Hope Scholar
2009     V-Foundation Scholar
2012       Leukemia and Lymphoma Society Scholar
2008     Susan G. Komen Scholar Award
2005     NCI K08 Mentored-Physician Scientist Award
2001      HHMI Physician-Scientist Fellowship Award

Feature Publications

​Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer.
Nature medicine Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Mahieu C, Anderton B, Eyob H, Kajimura S, Tward A, Krings G, Nomura DK, Goga A 


Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells.
Nature Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, Zhou A, Eyob H, Balakrishnan S, Wang CY, Yaswen P, Goga A, Werb Z 

MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition.
The Journal of experimental medicine Horiuchi D, Kusdra L, Huskey NE, Chandriani S, Lenburg ME, Gonzalez-Angulo AM, Creasman KJ, Bazarov AV, Smyth JW, Davis SE, Yaswen P, Mills GB, Esserman LJ, Goga A 

miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma.
Nature medicine Swarbrick A, Woods SL, Shaw A, Balakrishnan A, Phua Y, Nguyen A, Chanthery Y, Lim L, Ashton LJ, Judson RL, Huskey N, Blelloch R, Haber M, Norris MD, Lengyel P, Hackett CS, Preiss T, Chetcuti A, Sullivan CS, Marcusson EG, Weiss W, L'Etoile N, Goga A