B.S., Purdue University
Ph.D., University of Wisconsin
We have been investigating the involvement of the Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/GSK-3 and TP53 signaling pathways in breast, pancreatic, prostate, hepatocellular, and hematopoietic chemotherapeutic drug and radiation resistance. We have determined that altered expression of these pathways can increase resistance to both chemotherapeutic drugs and ionizing radiation. We are during the involvement of these pathways in cancer stem cells which we have been isolating from these different tumor types with the goal of being able to specifically target these pathways in the cancer stem cells. The PI3K/Akt pathway is also important in resistance to Tamoxifen therapy in breast cancer. This is important as the phosphatidylinositol-3 kinase (PI3K) gene(PIK3CA) is frequently mutated in breast cancer which results in Akt activation. This suggests that targeting PI3K may prove effective in therapy of drug, radiation and hormonal resistant breast cancer. We have determined that expression of mutated forms of the PTEN phosphatase and GSK-3beta kinase will increase the resistance of breast cancer cells to chemotherapeutic drugs and ionizing radiation. Thus these mutants act as dominant negative mutants to suppress the activity of the wild type protein. This novel discovery is important as mutations at the PTEN gene can occur in a heterozygous state and could act to silently increase chemo- and radio- resistance. We have determined that the lipid phosphatase as well as protein phosphatase activities of PTEN are important in determining resistance to chemotherapeutic drugs and ionizing radiation. This is important as it indicates that protein as well as lipid substrates are important in determining breast cancer chemo and radio sensitivity/resistance. Furthermore, we have determined that expression of dominant negative or wild-type TP53 will alter the chemo and radio-sensitivity of breast, pancreatic, prostate, hepatocellular and hematopoietic cells. Further analysis should provide clues into which genes and signaling pathways become activated or inactivated during the conversion of the breast, pancreatic, prostate and hematopoietic cancer cells into therapy resistant variants which may lead to more effective targeting. This is providing substantial rationale for the targeting of specific pathways in breast, pancreatic, prostate, hepatocellular and hematopoietic cancer.
Steelman LS, Navolanic PN, Sokolosky M, Taylor JR, Lehmann BD, Chappell WH, Abrams SL, Wong EW, Stadelman K, Terrian DM, Leslie N, Martelli AM, Stivala F, Libra M, Franklin RA, McCubrey JA. Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity of mTOR inhibitors. Oncogene 2008; 27: 4086-4095. PMID:18332865
McCubrey JA, Abrams SL, Ligresti G, Misaghian N, Wong ET, Basecke J, Troppmair J, Libra N, Nicoletti F, Molton S, McMahon M, Evangelisti C and Martelli AM. Involvement of p53 and Raf/MEK/ERK Pathways in Hematopoietic Drug Resistance. Leukemia 2008; 22: 2080-2090. PMID: 18685611
Steelman LS, Abrams SL, Shelton JG, Chappell WH, Bäsecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA. Dominantroles of the Raf/MEK/ERK pathway in cell cycle progression, prevention of apoptosis and sensitivity to chemotherapeutic drugs. Cell Cycle 2010; 9:1629-1638. PMID: 20372086
Abrams SL, Steelman LS, Shelton JG, Wong ET, Chappell WH, Bäsecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA. The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle 2010; 9: 1781-91. PMID: 20436278
Sokolosky ML, Stadelman KM, Chappell WH, Abrams SL, Martelli AM, Stivala F, Libra M, Nicoletti F, Drobot LB, Franklin RA, Steelman LS, McCubrey JA. Involvement of Akt-1 and mTOR in sensitivity of breast cancerto targeted therapy. Oncotarget 2011; 2: 538-50. PMID: 21730367.
Steelman LS, Navolanic P, Chappell WH, Abrams SL, Wong EWT, Martelli AM, Cocco L, Stivala F, Libra M, Nicoletti F, Drobot LB, Franklin RA and McCubrey JA. Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells. Cell Cycle 2011; 10; 3003-15.PMID: 21869603
Taylor JR, Lehmann BD, Chappell WH, Abrams SL, Steelman LS, McCubrey JA. Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells. Oncotarget. 2011; 2:610-26. PMID: 21881167
McCubrey JA, Abrams SL, Umezawa K, Cocco L, Martelli AM,Franklin RA, Chappell WH, Steelman LS. Novel approaches to target cancerinitiating cells-Eliminating the root of the cancer. Adv Enzyme Regul. 2012;52: 249-264. PMID: 21930143
Chappell WH, Abrams SL, Montalto G, Cervello M, MartelliAM, Candido S, Libra M, Polesel J, Talamini R, Arlinghaus R, Steelman LS,McCubrey JA. Effects of ectopic expression of NGAL on doxorubicin sensitivity.Oncotarget. 2012; 3: 1236-1245. PMID: 23100449
Chappell WH, Abrams SL, Franklin RA, Lahair MM, Montalto G, Cervello M, Martelli AM, Nicoletti F, Candido S, Libra M, Polesel J, Talamini R, Milella M, Tafuri A, Steelman LS, McCubrey JA. Ectopic NGAL expression can alter sensitivity of breast cancer cells to EGFR, Bcl-2, CaM-Kinhibitors and the plant natural product berberine. Cell Cycle. 2012; 11: 4447-4461.PMID: 23159854
Chappell WH, Lehmann BD, Terrian DM, Abrams SL, Steelman LS, McCubrey JA. p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3. Cell Cycle. 2012; 11: 4579-4588.PMID: 23187804
Sokolosky M, Chappell WH, Stadelman K, Abrams SL, Davis NM, Steelman LS, McCubrey JA. Inhibition of GSK-3β activity can result in drug and hormonal resistance and alter sensitivity to targeted therapy in MCF-7 breast cancer cells. Cell Cycle. 2014; 13:820-833. PMID:24407515
McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Sokolosky M, Abrams SL, Montalto G, D'Assoro AB, Libra M, Nicoletti F, Maestro R, Basecke J, Rakus D, Gizak A, Demidenko ZN, Cocco L, Martelli AM, Cervello M. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget. 2014; 5: 2881-2911. PMID:24931005
McCubrey JA, Abrams SL, Fitzgerald TL, Cocco L, Martelli AM, Montalto G, Cervello M, Scalisi A, Candido S, Libra M, Steelman LS. Rolesof signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis. Adv Biol Regul. 2015; 57:75-101. PMID:25453219.
Candido S, Abrams SL, Steelman LS, Lertpiriyapong K, Fitzgerald TL, Martelli AM, Cocco L, Montalto G, Cervello M, Polesel J, Libra M, McCubrey JA. Roles of NGAL and MMP-9 in the tumor microenvironment andsensitivity to targeted therapy. Biochim Biophys Acta. 2016; 1863:438-448.PMID: 26278055
Steelman LS, Fitzgerald T, Lertpiriyapong K, Cocco L, Follo MY, Martelli AM, Neri LM, Marmiroli S, Libra M, Candido S, Nicoletti F, Scalisi A, Fenga C, Drobot L, Rakus D, Gizak A, Laidler P, Dulińska-Litewka J, Basecke J, Mijatovic S, Maksimovic-Ivanic D, Montalto G, Cervello M, Milella M, Tafuri A, Demidenko Z, Abrams SL, McCubrey JA. Critical Roles of EGFR Family Members in Breast Cancer and Breast Cancer Stem Cells: Targets for Therapy. Curr Pharm Des. 2016; 22:2358-88. PMID: 26947958
Steelman LS, Martelli AM, Cocco L, Libra M, Nicoletti F, Abrams SL, and McCubrey JA. The therapeutic potential of mTOR inhibitors in breast cancer. British Journal of Clinical Pharmacology. 2016; 82:1189-1212.PMID: 27059645.
McCubrey JA, Rakus D, Gizak A, Steelman LS, Abrams SL, Lertpiriyapong K, Fitzgerald TL, Yang LV, Montalto G, Cervello M, Libra M, Nicoletti F, Scalisi A, Torino F, Fenga C, Neri LM, Marmiroli S, Cocco L, Martelli AM. Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer. Biochim Biophys Acta. 2016; 1863: 2942-2976. PMID: 27612668