Gayathri Devi

Overview:

Dr. Devi’s research interests include functional genomics, anti-cancer drug discovery and development, mechanisms of cancer cell signaling, tumor immunity and applications thereof for overcoming therapeutic resistance in cancer.

The lab has established prostate, inflammatory breast cancer and ovarian cellular and tumor models.

Positions:

Associate Professor in Surgery

Surgery, Surgical Sciences
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1998

University of Nebraska, College of Medicine

Grants:

Resveratrol, Carbohydrate Restriction and Prostate Cancer Progression

Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

GLI1 Inhibition to Enhance Chemo- and Targeted-Therapies in Inflammatory Breast Cancer

Awarded By
North Carolina Central University
Role
Principal Investigator
Start Date
End Date

Role of XIAP in Therapeutic Resistance in Inflammatory Breast Cancer

Awarded By
Dept. of the Army -- USAMRAA
Role
Principal Investigator
Start Date
End Date

Publications:

Adaptive stress response genes associated with breast cancer subtypes and survival outcomes reveal race-related differences.

Aggressive breast cancer variants, like triple negative and inflammatory breast cancer, contribute to disparities in survival and clinical outcomes among African American (AA) patients compared to White (W) patients. We previously identified the dominant role of anti-apoptotic protein XIAP in regulating tumor cell adaptive stress response (ASR) that promotes a hyperproliferative, drug resistant phenotype. Using The Cancer Genome Atlas (TCGA), we identified 46-88 ASR genes that are differentially expressed (2-fold-change and adjusted p-value < 0.05) depending on PAM50 breast cancer subtype. On average, 20% of all 226 ASR genes exhibited race-related differential expression. These genes were functionally relevant in cell cycle, DNA damage response, signal transduction, and regulation of cell death-related processes. Moreover, 23% of the differentially expressed ASR genes were associated with AA and/or W breast cancer patient survival. These identified genes represent potential therapeutic targets to improve breast cancer outcomes and mitigate associated health disparities.
Authors
Al Abo, M; Gearhart-Serna, L; Van Laere, S; Freedman, JA; Patierno, SR; Hwang, E-SS; Krishnamurthy, S; Williams, KP; Devi, GR
MLA Citation
Al Abo, Muthana, et al. “Adaptive stress response genes associated with breast cancer subtypes and survival outcomes reveal race-related differences.Npj Breast Cancer, vol. 8, no. 1, June 2022, p. 73. Pubmed, doi:10.1038/s41523-022-00431-z.
URI
https://scholars.duke.edu/individual/pub1524865
PMID
35697736
Source
pubmed
Published In
Npj Breast Cancer
Volume
8
Published Date
Start Page
73
DOI
10.1038/s41523-022-00431-z

Comparative transcriptional analyses of preclinical models and patient samples reveal MYC and RELA driven expression patterns that define the molecular landscape of IBC.

Inflammatory breast cancer (IBC) is an aggressive disease for which the spectrum of preclinical models was rather limited in the past. More recently, novel cell lines and xenografts have been developed. This study evaluates the transcriptome of an extended series of IBC preclinical models and performed a comparative analysis with patient samples to determine the extent to which the current models recapitulate the molecular characteristics of IBC observed clinically. We demonstrate that the IBC preclinical models are exclusively estrogen receptor (ER)-negative and of the basal-like subtype, which reflects to some extent the predominance of these subtypes in patient samples. The IBC-specific 79-signature we previously reported was retrained and discriminated between IBC and non-IBC preclinical models, but with a relatively high rate of false positive predictions. Further analyses of gene expression profiles revealed important roles for cell proliferation, MYC transcriptional activity, and TNFɑ/NFκB in the biology of IBC. Patterns of MYC expression and transcriptional activity were further explored in patient samples, which revealed interactions with ESR1 expression that are contrasting in IBC and nIBC and notable given the comparatively poor outcomes of ER+ IBC. Our analyses also suggest important roles for NMYC, MXD3, MAX, and MLX in shaping MYC signaling in IBC. Overall, we demonstrate that the IBC preclinical models can be used to unravel cancer cell intrinsic molecular features, and thus constitute valuable research tools. Nevertheless, the current lack of ER-positive IBC models remains a major hurdle, particularly since interactions with the ER pathway appear to be relevant for IBC.
Authors
Rypens, C; Bertucci, F; Finetti, P; Robertson, F; Fernandez, SV; Ueno, N; Woodward, WA; Van Golen, K; Vermeulen, P; Dirix, L; Viens, P; Birnbaum, D; Devi, GR; Cristofanilli, M; Van Laere, S
MLA Citation
Rypens, Charlotte, et al. “Comparative transcriptional analyses of preclinical models and patient samples reveal MYC and RELA driven expression patterns that define the molecular landscape of IBC.Npj Breast Cancer, vol. 8, no. 1, Jan. 2022, p. 12. Pubmed, doi:10.1038/s41523-021-00379-6.
URI
https://scholars.duke.edu/individual/pub1506983
PMID
35042871
Source
pubmed
Published In
Npj Breast Cancer
Volume
8
Published Date
Start Page
12
DOI
10.1038/s41523-021-00379-6

Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.

Serine/threonine kinase 3 (STK3) is an essential member of the highly conserved Hippo tumor suppressor pathway that regulates Yes-associated protein 1 (YAP1) and TAZ. STK3 and its paralog STK4 initiate a phosphorylation cascade that regulates YAP1/TAZ inhibition and degradation, which is important for regulated cell growth and organ size. Deregulation of this pathway leads to hyperactivation of YAP1 in various cancers. Counter to the canonical tumor suppression role of STK3, we report that in the context of prostate cancer (PC), STK3 has a pro-tumorigenic role. Our investigation started with the observation that STK3, but not STK4, is frequently amplified in PC. Additionally, high STK3 expression is associated with decreased overall survival and positively correlates with androgen receptor (AR) activity in metastatic castrate-resistant PC. XMU-MP-1, an STK3/4 inhibitor, slowed cell proliferation, spheroid growth, and Matrigel invasion in multiple models. Genetic depletion of STK3 decreased proliferation in several PC cell lines. In a syngeneic allograft model, STK3 loss slowed tumor growth kinetics in vivo, and biochemical analysis suggests a mitotic growth arrest phenotype. To further probe the role of STK3 in PC, we identified and validated a new set of selective STK3 inhibitors, with enhanced kinase selectivity relative to XMU-MP-1, that inhibited tumor spheroid growth and invasion. Consistent with the canonical role, inhibition of STK3 induced cardiomyocyte growth and had chemoprotective effects. Our results indicate that STK3 has a non-canonical role in PC progression and that inhibition of STK3 may have a therapeutic potential for PC that merits further investigation.
Authors
Schirmer, AU; Driver, LM; Zhao, MT; Wells, CI; Pickett, JE; O'Bryne, SN; Eduful, BJ; Yang, X; Howard, L; You, S; Devi, GR; DiGiovanni, J; Freedland, SJ; Chi, J-T; Drewry, DH; Macias, E
MLA Citation
Schirmer, Amelia U., et al. “Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.Mol Ther, vol. 30, no. 1, Jan. 2022, pp. 485–500. Pubmed, doi:10.1016/j.ymthe.2021.08.029.
URI
https://scholars.duke.edu/individual/pub1494995
PMID
34450249
Source
pubmed
Published In
Molecular Therapy : the Journal of the American Society of Gene Therapy
Volume
30
Published Date
Start Page
485
End Page
500
DOI
10.1016/j.ymthe.2021.08.029

Analysis of polycyclic aromatic hydrocarbon intake in the US adult population from NHANES 2005-2014 identifies vulnerable subpopulations, suggests interaction between tobacco smoke exposure and sociodemographic factors.

Polycyclic aromatic hydrocarbons (PAHs) are a toxic and ubiquitous class of environmental chemicals, products of fuel combustion from human and natural sources. The objective of this study was to identify vulnerable populations for high PAH exposure and variability, to better understand where to target PAH exposure reduction initiatives. Urinary metabolite data were collected from 9517 individuals from the U.S. CDC National Health and Nutrition Examination Survey years 2005-2014 for four parental PAHs naphthalene, fluorene, phenanthrene, and pyrene. We utilized these urinary biomarkers to estimate PAH intake, and regression models were fit for multiple demographic and lifestyle variables, to determine variable effects, interactions, odds of high versus low PAH intake. Smoking and secondhand smoke exposure accounted for the largest PAH intake rate variability (25.62%), and there were strongest interactions between race/ethnicity and smoking or SHS exposure, reflected in a much greater contribution of smoking to PAH intake in non-Hispanic Whites as compared to other races/ethnicities. Increased odds of high PAH intake were seen in older age groups, obese persons, college graduates, midrange incomes, smokers, and those who were SHS exposed. Among the non-smoking population, effects of other demographic factors lessened, suggesting a highly interactive nature. Our results suggest that there are demographic subpopulations with high PAH intake as a result of different smoking behaviors and potentially other exposures. This has human health, environmental justice, and regulatory implications wherein smoking cessation programs, SHS exposure regulations, and public health initiatives could be better targeted towards vulnerable subpopulations to meaningfully reduce PAH exposures.
Authors
Gearhart-Serna, LM; Tacam, M; Slotkin, TA; Devi, GR
URI
https://scholars.duke.edu/individual/pub1487567
PMID
34216610
Source
pubmed
Published In
Environ Res
Volume
201
Published Date
Start Page
111614
DOI
10.1016/j.envres.2021.111614

Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy.

XIAP, the most potent inhibitor of cell death pathways, is linked to chemotherapy resistance and tumor aggressiveness. Currently, multiple XIAP-targeting agents are in clinical trials. However, the characterization of XIAP expression in relation to clinicopathological variables in large clinical series of breast cancer is lacking. We retrospectively analyzed non-metastatic, non-inflammatory, primary, invasive breast cancer samples for XIAP mRNA (n = 2341) and protein (n = 367) expression. XIAP expression was analyzed as a continuous value and correlated with clinicopathological variables. XIAP mRNA expression was heterogeneous across samples and significantly associated with younger patients' age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, HR+/HER2- status, and PAM50 luminal B subtype. Higher XIAP expression was associated with shorter DFS in uni- and multivariate analyses in 909 informative patients. Very similar correlations were observed at the protein level. This prognostic impact was significant in the HR+/HER2- but not in the TN subtype. Finally, XIAP mRNA expression was associated with lower pCR rate to anthracycline-based neoadjuvant chemotherapy in both uni- and multivariate analyses in 1203 informative patients. Higher XIAP expression in invasive breast cancer is independently associated with poorer prognosis and resistance to chemotherapy, suggesting the potential therapeutic benefit of targeting XIAP.
Authors
Devi, GR; Finetti, P; Morse, MA; Lee, S; de Nonneville, A; Van Laere, S; Troy, J; Geradts, J; McCall, S; Bertucci, F
MLA Citation
Devi, Gayathri R., et al. “Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy.Cancers (Basel), vol. 13, no. 11, June 2021. Pubmed, doi:10.3390/cancers13112807.
URI
https://scholars.duke.edu/individual/pub1484291
PMID
34199946
Source
pubmed
Published In
Cancers
Volume
13
Published Date
DOI
10.3390/cancers13112807

Research Areas:

Muser Mentor