Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance.

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Published in Oncotarget on October 01, 2012

Authors

James A McCubrey1, Linda S Steelman, William H Chappell, Stephen L Abrams, Richard A Franklin, Giuseppe Montalto, Melchiorre Cervello, Massimo Libra, Saverio Candido, Grazia Malaponte, Maria C Mazzarino, Paolo Fagone, Ferdinando Nicoletti, Jörg Bäsecke, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Michele Milella, Agostino Tafuri, Francesca Chiarini, Camilla Evangelisti, Lucio Cocco, Alberto M Martelli

Author Affiliations

1: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.

Associated clinical trials:

Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212 | NCT01072175

A Study of Vemurafenib in Previously Treated Patients With Metastatic Melanoma | NCT00949702

Safety, Pharmacokinetics and Pharmacodynamics of BEZ235 Plus MEK162 in Selected Advanced Solid Tumor Patients | NCT01337765

A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer | NCT00620594

Study to Determine the Effectiveness of GSK1120212 in BRAF Mutation-positive Melanoma Previously Treated With or Without a BRAF Inhibitor | NCT01037127

A Phase Ib Study of MEK162 Plus BYL719 in Adult Patients With Selected Advanced Solid Tumors | NCT01449058

A Phase I Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2118436 in Subjects With Solid Tumors | NCT00880321

A Combination Therapy Study of MK-2206 and AZD6244 in Participants With Advanced Solid Tumors (MK-2206-010) | NCT01021748

A Study of BYL719 in Adult Patients With Advanced Solid Malignancies, Whose Tumors Have an Alteration of the PIK3CA Gene | NCT01219699

A Study of XL765 (SAR245409) in Combination With Temozolomide With and Without Radiation in Adults With Malignant Gliomas | NCT00704080

A Study of Zelboraf (Vemurafenib) in Patients With BRAF V600 Mutation-Positive Cancers | NCT01524978

A Study to Evaluate RAF265, an Oral Drug Administered to Subjects With Locally Advanced or Metastatic Melanoma (CHIR-265-MEL01) | NCT00304525

Study of GDC-0941 or GDC-0980 With Fulvestrant Versus Fulvestrant in Advanced or Metastatic Breast Cancer in Participants Resistant to Aromatase Inhibitor Therapy | NCT01437566

Clinical Study Of PI3K/mTOR Inhibitors In Combination With An Oral MEK Inhibitor Or Irinotecan In Patients With Advanced Cancer | NCT01347866

Safety Study of XL765 (SAR245409) in Combination With Erlotinib in Adults With Solid Tumors | NCT00777699

Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors | NCT01390818

Metformin and Temsirolimus in Treating Patients With Metastatic or Unresectable Solid Tumor or Lymphoma | NCT00659568

Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia | NCT01371981

Study of the Safety and Pharmacokinetics of XL765 (SAR245409) in Adults With Solid Tumors | NCT00485719

Study of Oral OSI-027 in Patients With Advanced Solid Tumors or Lymphoma | NCT00698243

Selumetinib and Akt Inhibitor MK2206 in Treating Patients With Stage III or Stage IV Melanoma Who Failed Prior Therapy With Vemurafenib or Dabrafenib | NCT01519427

A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma | NCT01153763

Study to Investigate Idelalisib in Combination With Chemotherapeutic Agents, Immunomodulatory Agents and Anti-CD20 Monoclonal Antibody (mAb) in Subjects With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia | NCT01088048

Dose Escalation Study of MLN0128 in Combination With Paclitaxel, With/Without Trastuzumab, in Subjects With Advanced Solid Malignancies | NCT01351350

Dose Escalation Study of MLN0128 in Subjects With Advanced Malignancies | NCT01058707

Safety, Pharmacokinetics (PK) of AKT and MEK Combination | NCT01138085

Dose Defining Study For MK-2206 Combined With Gefitinib In Non Small Cell Lung Cancer (NSCLC) | NCT01147211

7-Hydroxystaurosporine and Perifosine in Treating Patients With Relapsed or Refractory Acute Leukemia, Chronic Myelogenous Leukemia or High Risk Myelodysplastic Syndromes | NCT00301938

A Phase I Study of MK2206 in Combination With Standard Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors (2206-003 AM5) | NCT00848718

MEK162 and RAF265 in Adult Patients With Advanced Solid Tumors Harboring RAS or BRAFV600E Mutations | NCT01352273

Akt Inhibitor MK2206 in Combination With Lapatinib Ditosylate in Patients With Advanced or Metastatic Solid Tumors or Breast Cancer | NCT01245205

A Study of Dalotuzumab + MK-2206, Dalotuzumab + MK-0752, and Dalotuzumab + MK-8669 Combination Therapies in Participants With Advanced Cancer (MK-0646-027) | NCT01243762

MK2206 in Combination With Anastrozole, Fulvestrant, or Anastrozole and Fulvestrant in Treating Postmenopausal Women With Metastatic Breast Cancer | NCT01344031

A Study Of Two Dual PI3K/mTOR Inhibitors, PF-04691502 And PF-05212384 In Patients With Recurrent Endometrial Cancer | NCT01420081

Selumetinib and Erlotinib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer | NCT01222689

AZD8055 for Adults With Recurrent Gliomas | NCT01316809

Dose Escalation Study of MLN0128 in Relapsed or Refractory Multiple Myeloma or Waldenstrom Macroglobulinemia | NCT01118689

Exploratory Study of XL765 (SAR245409) or XL147 (SAR245408) in Subjects With Recurrent Glioblastoma Who Are Candidates for Surgical Resection | NCT01240460

Dose Finding Study of RAD001 (Everolimus, Afinitor®) in Combination With BEZ235 in Patients With Advanced Solid Tumors | NCT01482156

MK2206 and Paclitaxel in Treating Patients With Locally Advanced or Metastatic Solid Tumors or Metastatic Breast Cancer | NCT01263145

Trial of Gemcitabine, Carboplatin, and Sorafenib in Chemotherapy-naive Patients With Advanced/Metastatic Bladder Carcinoma | NCT00461851

A Trial of Oral BEZ235 and BKM120 in Combination With Paclitaxel With or Without Trastuzumab | NCT01285466

Lapatinib Ditosylate and Akt Inhibitor MK2206 in Treating Women With Metastatic Breast Cancer | NCT01281163

Triciribine Phosphate Monohydrate (TCN-PM, VD-0002) in Adult Patients With Advanced Hematologic Malignancies | NCT00642031

Trial of Pimasertib in Hematological Malignancies | NCT00957580

A Study of MK2206 in Combination With Trastuzumab and Lapatinib for the Treatment of HER2+ Solid Tumors (2206-015) | NCT00963547

Phase I Study of Triciribine Phosphate Monohydrate (TCN-PM, VD-0002) in Adult Subjects With Metastatic Cancer | NCT00363454

A Study of BEZ235 in Adult Japanese Patients With Advanced Solid Tumors | NCT01195376

Cytarabine and UCN-01 in Treating Patients With Refractory or Relapsed Acute Myelogenous Leukemia or Myelodysplastic Syndrome | NCT00004263

Phase I Study of Palomid 529 a Dual TORC1/2 Inhibitor of the PI3K/Akt/mTOR Pathway for Advanced Neovascular Age-Related Macular Degeneration (P52901) | NCT01033721

A Study of BYL719 in Adult Patients With Advanced Solid Malignancies | NCT01387321

Akt Inhibitor MK2206, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma | NCT01369849

Sorafenib Plus Tegafur/Uracil (UFUR®) for Hepatocellular Carcinoma (HCC) | NCT00464919

RDEA119 and Sorafenib Combination Dose Escalation Study | NCT00785226

Study of PI3 Kinase/mTOR Inhibitor BEZ235 Twice Daily for Advanced Solid Tumors | NCT01343498

A Rollover Study to Provide Continued Treatment With GSK2118436 to Subjects With BRAF Mutation-Positive Tumors | NCT01231594

Pharmacodynamic Study of BKM120 in Breast Cancer | NCT01513356

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PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. Proc Natl Acad Sci U S A (2011) 2.14

The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox. Cell Cycle (2010) 2.10

Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival. Blood (2005) 2.09

A small peptide mimicking the key domain of MEPE/OF45 interacting with CHK1 protects human cells from radiation-induced killing. Cell Cycle (2010) 2.06

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