Identification of mutations in receptor and non-receptor protein kinases that drive malignant transformation of cancer cells ('driver'mutations) have revolutionized patient care by opening the door to patient-tailored targeted therapies that can improve patient survival. In order to discover new targets for therapy, we sequenced the coding regions of -100 melanomas and identified a large number of somatic mutations and inherited Single Nucleotide Variants (SNVs). One of the most important findings of this effort is the identification ofthe """"""""RAC1 signaling pathway"""""""" as a potential new target for melanoma therapy. The analysis revealed a recurrent, UV signature activating mutation in this RHO family of small GTPases, RAC[P29S], in ~5% of melanomas, in addition, the sequencing data revealed mutations in upstream regulators and downstream effectors of RAC1 pathway in a large numbers of melanoma tumors. Functional studies demonstrated an important role in proliferation and migration of not only mutant but also melanoma cells that that donot harbor the P29S mutation. The data suggest that pharmacological inhibition of RACl or its critical effeGtor(s) can be applied for development of new therapies for melanoma patients. The general goals ofthis project are to determine the frequency and prognostic significance of RAC[P29S] mutation in sun exposed melanocytic lesions, and to identify downstream effectors of RACl most likely to be druggable targets in this pathway.
The specific aims are:
Aim 1 : To determine the frequency of RAC1[P29S] mutation and RACl expression levels in a large cohort of melanocytic lesions and correlate with pathological features and tumor progression;
Aim 2 : To elucidate the downstream targets of activated RACl in melanomas.
Aim 3 : To identify small-molecule inhibitors of PAK kinases, the RACl effectors. These studies are likely to provide new opportunities for drug discovery for melanomas and possibly other cancers that can facilitate patienttailored targeted therapy.

Public Health Relevance

There is a need for new patient-tailored therapy for melanoma. Treatment of melanoma patients carrying BRAF[V600E/K] mutations with vemurafenib (PLX4032/RG7204), renamed Zelboraf, yields a very high response rate, but the disease tends to relapse. The novel regulatory pathway discovered by exome sequencing and validated by functional analyses provides the opportunity for additional therapeutic targets for patients who do not benefit from current therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA121974-06A1
Application #
8389779
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
2006-06-01
Project End
2017-08-31
Budget Start
2012-09-19
Budget End
2013-08-31
Support Year
6
Fiscal Year
2012
Total Cost
$166,133
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kluger, Harriet M; Zito, Christopher R; Turcu, Gabriela et al. (2017) PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors. Clin Cancer Res 23:4270-4279
Cyrenne, Benoit M; Lewis, Julia M; Weed, Jason G et al. (2017) Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients. Blood 130:2073-2083
Weed, Jason; Gibson, Juliet; Lewis, Julia et al. (2017) FISH Panel for Leukemic CTCL. J Invest Dermatol 137:751-753
Lazova, Rossitza; Pornputtapong, Natapol; Halaban, Ruth et al. (2017) Spitz nevi and Spitzoid melanomas: exome sequencing and comparison with conventional melanocytic nevi and melanomas. Mod Pathol 30:640-649
Zhang, Yanchang; Cartmel, Brenda; Choy, Courtney C et al. (2017) Body mass index, height and early-onset basal cell carcinoma in a case-control study. Cancer Epidemiol 46:66-72
Cartmel, B; Bale, A E; Mayne, S T et al. (2017) Predictors of tanning dependence in white non-Hispanic females and males. J Eur Acad Dermatol Venereol 31:1223-1228
Stiegler, Amy L; Boggon, Titus J (2017) p190RhoGAP proteins contain pseudoGTPase domains. Nat Commun 8:506
Wu, Mengyun; Zang, Yangguang; Zhang, Sanguo et al. (2017) Accommodating missingness in environmental measurements in gene-environment interaction analysis. Genet Epidemiol 41:523-554
Kahn, Jessica A; Lee, Jeannette; Belzer, Marvin et al. (2017) HIV-Infected Young Men Demonstrate Appropriate Risk Perceptions and Beliefs about Safer Sexual Behaviors after Human Papillomavirus Vaccination. AIDS Behav :
Miller, Chad J; Muftuoglu, Yagmur; Turk, Benjamin E (2017) A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases. Biochem Pharmacol 142:39-45

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