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Thomas Jefferson University - Andrew E. Aplin, PhD
Andrew E. Aplin, PhD

Cancer Biology
Professor
Department of Cancer Biology
Kimmel Cancer Center
Mailing Address
233 South 10th Street
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: 215-503-7296
Fax: 215-923-9248
Andrew.Aplin@KimmelCancerCenter.Org
Expertise and Research Interests
Malignant melanoma is the deadliest form of skin cancer and its incidence is increasing. Melanoma arises from epidermal melanocytes, the pigment producing cells in the skin. Currently, melanoma metastasis is only preventable by early detection and surgical excision of primary tumors; hence, there is an immediate need to understand the mechanisms underlying melanocyte transformation. We utilize molecular and clinical grade inhibitor approaches to alter key signaling pathway in primary human melanocytes and a panel of melanoma cells characterizing different stages of melanoma progression. We test the role of target proteins in 2D and 3D dermal mimetic in vitro systems and an intradermal in vivo model.

The serine/threonine kinase, B-RAF, is somatically mutated in 50% of melanomas. Mutant B-RAF hyper-activates signaling, which is required for melanoma growth and invasion. One focus in the laboratory is determining the effectors of the mutant B-RAF signaling pathway that elicit malignant traits in melanoma cells. We are identifying mechanisms of pro-survival signaling via alterations in Bcl-2 family proteins and BH-3-only proteins. Additionally, we are investigating the function of Rho family GTPases, epithelial-to-mesenchymal transition (EMT) transcription factors and integrin-mediated signaling in melanoma cell invasion and migration. Other projects are analyzing the signaling pathways downstream of mutant NRAS, which is altered in 15% of melanomas in a manner that is mutually exclusive from B-RAF.

RAF inhibitors have recently been FDA-approved for the treatment of mutant B-RAF melanoma patients. Despite eliciting tumor shrinkage in the majority of patients, approximately 15% of patients do not initially respond and most of the original responders are now eliciting drug resistance. These modes of resistance are major obstacles to the prolonged effects of RAF inhibitor-based therapies. We are elucidating mechanisms of resistance to RAF inhibitors and have focused on FOXD3, a stemness factor. FOXD3 is up-regulated in mutant B-RAF melanoma cells following targeting of the B-RAF-MEK-ERK1/2 signaling pathway and FOXD3 up-regulation provides adaptive drug tolerance to RAF inhibitors. The mechanism of FOXD3 action is an avenue of current investigation. Ultimately, we expect to identify novel strategies for therapeutic intervention in mutant BRAF melanomas.
Keywords
Melanoma; B-RAF; N-RAS; Tumor microenvironment; Resistance to RAF inhibitors; Rho family GTPases.
Publications
  • Abel, E.V. and Aplin, A.E. (2010) FOXD3 is a mutant B-RAF-regulated inhibitor of G1/S progression in melanoma cells. Cancer Res. 70: 2891-2900.
  • Shao, Y. and Aplin, A.E. (2010) Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res. 70: 6670-81.
  • Kaplan, F.M., Mastrangelo, M.J. and Aplin, A.E. (2010) The wrath of RAFs: rogue behavior of B-RAF kinase inhibitors. J. Investigative Dermatol. 30: 2669-71.
  • Weiss, M.B. and Aplin. A.E. (2010) Paying "particle" attention to novel melanoma treatment strategies. J. Investigative Dermatol. 130: 2699-701.
  • Aplin, A.E. and Sato, T. (2011) Mind the Bap. Pigment Cell and Melanoma Res. 24:6-7.
  • Kaplan, F.M., Shao, Y., Mayberry, M. and Aplin, A.E. (2011) Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by PLX4720 in mutant N-RAS melanoma cells. Oncogene 30:366-71.
  • Katiyar, P. and Aplin, A.E. (2011) FOXD3 regulates migratory properties and Rnd3 expression in melanoma cells. Mol Cancer Res. 9:545-52.
  • Aplin, A.E., Kaplan, F. M. and Shao, Y.P. (2011) Mechanisms of resistance to RAF inhibitors in melanoma. J. Investigative Dermatol. 131:1817-20.
  • Abel, E.V. and Aplin, A.E. (2011) Finding the root of the problem: the quest to identify melanoma cells. Frontiers in Biosciences 3:937-45.
  • Basile, K.J., Abel, E.V., and Aplin, A.E. (2012) Adaptive up-regulation of FOXD3 promotes resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells. Oncogene 31:2471-9.
  • Shao, Y. and Aplin, A.E. (2012) ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity. Cell Death & Disease. Jan 19 [Epub ahead of print].
  • Vu, H.L., and Aplin, A.E. (2012). The Yin-Yang of RAF inhibitors Pigment Cell and Melanoma Research. 25:127-8.
  • Shao, Y, and Aplin A.E. (2012) BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma. Cell Death Diff. doi: 10.1038/cdd.2012.94. [Epub ahead of print].

Individual Expertise profile of Andrew E. Aplin, PhD, Copyright © Andrew E. Aplin, PhD.
Last Updated by Andrew Aplin, PhD : Monday, August 13, 2012 8:57:27 AM



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