Memorial Hospital Research Laboratories // Human Oncology & Pathogenesis Program

David B. Solit, MD

The focus of my laboratory is the development of cancer therapies that target pathways responsible for cancer initiation and progression. I am particularly interested in the study of cancers dependent upon alterations in tyrosine kinase and steroid receptor signaling. In pursuit of this goal, we have established relevant model systems in which changes in a drugs proposed molecular target can be correlated with drug dose, serum level, and anticancer activity. Our hypothesis is that the consequences of pathway inhibition will vary as a function of cell lineage and the complement of mutations within a tumor cells. Therefore, in order to improve the treat of cancer patients, one must understand not only which genetic changes are commonly found within particular tumor types but the mechanisms whereby these genetic alterations support tumor growth, survival, metastasis or other hallmarks of the cancer phenotype.

One focus of the laboratory is understanding the role played by activated Ras and Raf in mediating transformation. The RAS/RAF/MEK/ERK cascade (MAPK pathway) transduces growth factor initiated signals that regulate cell proliferation and survival. Constitutive activation of this pathway is a common event in human tumors and activating mutations in this pathway occur in Ras, B-Raf and upstream receptor tyrosine kinases (RTK) in a mutually exclusive fashion. We find that tumor cells with activating BRAF mutations are selectively sensitivity to MEK inhibition (Solit et al., Nature 2006). Tumors in which MAP kinase is activated by other upstream activating mutations (RAS, RTKs, unknown) are typically less sensitive or resistant to MEK inhibition.

Using pharmacologic and genetic methods, current studies are focused on identifying which downstream effector pathways are most responsible for mediating growth and survival in tumors with Ras and B-Raf mutations. These studies are of interest as selective inhibitors of these downstream pathways are currently being testing in patients at MSKCC and elsewhere. Concurrent mutations that mediate resistance to Raf and MEK inhibitors are also being studied using preclinical model systems and human tumor samples. One goal of such studies is to use the data generated to develop rational combination therapies.

Publications

Xing F, Persaud Y, Pratilas CA, Taylor BS, Janakiraman M, She QB, Gallardo H, Liu C, Merghoub T, Hefter B, Dolgalev I, Viale A, Heguy A, De Stanchina E, Cobrinik D, Bollag G, Wolchok J, Houghton A, Solit DB. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene. 2012 Jan 26;31(4):446-57. doi: 10.1038/onc.2011.250. Epub 2011 Jul 4.

Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011 Nov 23;480(7377):387-90. doi: 10.1038/nature10662.

Hanrahan AJ, Schultz N, Westfal ML, Sakr RA, Giri DD, Scarperi S, Janakiraman M, Olvera N, Stevens EV, She QB, Aghajanian C, King TA, Stanchina Ed, Spriggs DR, Heguy A, Taylor BS, Sander C, Rosen N, Levine DA, Solit DB. Genomic complexity and AKT dependence in serous ovarian cancer. Cancer Discov. 2012 Jan;2(1):56-67. doi: 10.1158/2159-8290.CD-11-0170.

Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, Bencardino K, Cercek A, Chen CT, Veronese S, Zanon C, Sartore-Bianchi A, Gambacorta M, Gallicchio M, Vakiani E, Boscaro V, Medico E, Weiser M, Siena S, Di Nicolantonio F, Solit D, Bardelli A. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012 Jun 28;486(7404):532-6. doi: 10.1038/nature11156.

Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012 Oct 12;338(6104):221. doi: 10.1126/science.1226344. Epub 2012 Aug 23.

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