Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition

Mutations of the BRAF gene in human cancer

Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674

Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors

Chou, T.-C., & Talalay, P. (1984) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(84)90007-4 · Cited by 7,178

AKT/PKB signaling: navigating downstream

Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115

Targeting RAS signalling pathways in cancer therapy

Downward, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc969 · Cited by 3,354

Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

Roberts, P. J., & Der, C. J. (2007) · Oncogene · doi:10.1038/sj.onc.1210422 · Cited by 2,788

Targeting the phosphoinositide 3-kinase pathway in cancer

Liu, P., Cheng, H.-L. M., Roberts, T. M., & Zhao, J. J. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2926 · Cited by 2,785

Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance

McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Wong, E. W. T., Chang, F., Lehmann, B. D., Terrian, D. M., Milella, M., Tafuri, A., et al. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.10.001 · Cited by 2,349

Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., Maira, M., McNamara, K., Perera, S. A., Song, Y., et al. (2008) · Nature Medicine · doi:10.1038/nm.1890 · Cited by 1,330

BRAF mutation predicts sensitivity to MEK inhibition

Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G. A., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., et al. (2005) · Nature · doi:10.1038/nature04304 · Cited by 1,326

The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website

Bamford, S., Dawson, E., Forbes, S. A., Clements, J., Pettett, R., Doǧan, A., Flanagan, A. M., Teague, J. W., Futreal, P. A., Stratton, M. R., et al. (2004) · British Journal of Cancer · doi:10.1038/sj.bjc.6601894 · Cited by 1,248

The RAF proteins take centre stage

Wellbrock, C., Karasarides, M., & Marais, R. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1498 · Cited by 1,223

Bim: a novel member of the Bcl‐2 family that promotes apoptosis

O’Connor, L., Strasser, A., O’Reilly, L. A., Hausmann, G., Adams, J. M., Cory, S., & Huang, D. C. S. (1998) · The EMBO Journal · doi:10.1093/emboj/17.2.384 · Cited by 1,163

The Identification of 2-(1 H -Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2- d ]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer

Folkes, A. J., Ahmadi, K., ALDERTON, W. K., Alix, S., Baker, S. J., Box, G., Chuckowree, I., Clarke, P. A., Depledge, P., Eccles, S. A., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800295d · Cited by 756

The PIK3CA gene is mutated with high frequency in human breast cancers

Bachman, K. E., Argani, P., Samuels, Y., Silliman, N., Ptak, J., Szabo, S., Konishi, H., Karakas, B., Blair, B. G., Lin, C., et al. (2004) · Cancer Biology & Therapy · doi:10.4161/cbt.3.8.994 · Cited by 665

Oncogenic Mutations of PIK3CA in Human Cancers

Samuels, Y., & Velculescu, V. E. (2004) · Cell Cycle · doi:10.4161/cc.3.10.1164 · Cited by 551

Mutation of the PIK3CA oncogene in human cancers

Karakas, B., Bachman, K. E., & Park, B. H. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6602970 · Cited by 505

In vivo Antitumor Activity of MEK and Phosphatidylinositol 3-Kinase Inhibitors in Basal-Like Breast Cancer Models

Hoeflich, K. P., O'Brien, C. L., Boyd, Z. S., Cavet, G., Guerrero, S., Jung, K., Januario, T., Savage, H. M., Punnoose, E. A., Truong, T., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0317 · Cited by 474

4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors

She, Q.-B., Halilovic, E., Ye, Q., Zhen, W., Shirasawa, S., Sasazuki, T., Solit, D. B., & Rosen, N. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.05.023 · Cited by 400

Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

Mirzoeva, O. K., Das, D., Heiser, L. M., Bhattacharya, S., Siwak, D. R., Gendelman, R., Bayani, N., Wang, N. J., Neve, R. M., Guan, Y., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3389 · Cited by 387

Strategies for optimizing combinations of molecularly targeted anticancer agents

Dancey, J. E., & Chen, H. X. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2089 · Cited by 369

Pharmacokinetic variability of anticancer agents

Undevia, S. D., Gomez-Abuin, G., & Ratain, M. J. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1629 · Cited by 261

Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer

Sos, M. L., Fischer, S., Ullrich, R. T., Peifer, M., Heuckmann, J. M., Koker, M., Heynck, S., Stückrath, I., Weiss, J. M., Fischer, F., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907325106 · Cited by 258

Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models

O'Brien, C. L., Wallin, J. J., Sampath, D., GuhaThakurta, D., Savage, H. M., Punnoose, E. A., Guan, J., Berry, L., Prior, W. W., Amler, L. C., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2828 · Cited by 256

Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements

Kummar, S., Chen, H. X., Wright, J., Holbeck, S. L., Millin, M. D., Tomaszewski, J. E., Zweibel, J., Collins, J. M., & Doroshow, J. H. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3216 · Cited by 254

From basic research to clinical development of MEK1/2 inhibitors for cancer therapy

Frémin, C., & Meloche, S. (2010) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-3-8 · Cited by 249

BRAF Signaling and Targeted Therapies in Melanoma

Dhomen, N. S., & Marais, R. (2009) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2009.04.001 · Cited by 208

Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic

Cragg, M. S., Jansen, E. S., Cook, M., Harris, C., Strasser, A., & Scott, C. L. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35437 · Cited by 207

Antitumor Efficacy of the Novel RAF Inhibitor GDC-0879 Is Predicted by BRAFV600E Mutational Status and Sustained Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase Pathway Suppression

Hoeflich, K. P., Herter, S., Tien, J., Wong, L. L.-Y., Berry, L., Chan, J., O'Brien, C. L., Modrusan, Z. D., Seshagiri, S., Lackner, M. R., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3563 · Cited by 173

Bim and Bmf in tissue homeostasis and malignant disease

Hofbauer, J. P., Labi, V., Egle, A., & Villunger, A. (2008) · Oncogene · doi:10.1038/onc.2009.42 · Cited by 150

Therapeutic Potential of Phosphoinositide 3-Kinase Inhibitors

Ward, S. G., Sotsios, Y., Dowden, J., Bruce, I., & Finan, P. M. (2003) · Chemistry & Biology · doi:10.1016/s1074-5521(03)00048-6 · Cited by 124

Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Inhibition and Biomarker Modulation by the Novel Phosphatidylinositol 3-Kinase Inhibitor GDC-0941

Salphati, L., Wong, H., Belvin, M. P., Bradford, D., Edgar, K. A., Prior, W. W., Sampath, D., & Wallin, J. J. (2010) · Drug Metabolism and Disposition · doi:10.1124/dmd.110.032912 · Cited by 86

Development of Phosphoinositide-3 Kinase Pathway Inhibitors for Advanced Cancer

Cleary, J. M., & Shapiro, G. I. (2010) · Current Oncology Reports · doi:10.1007/s11912-010-0091-6 · Cited by 65

The role of phosphoinositide 3-kinase in human disease.

Cantley, L. C. (2006) · PubMed · Cited by 22

Preclinical disposition and pharmacokinetics-pharmacodynamic modeling of biomarker response and tumour growth inhibition in xenograft mouse models of G-573, a MEK inhibitor

Choo, E. F., Belvin, M. P., Chan, J., Hoeflich, K. P., Orr, C., Robarge, K. D., Yang, X., Zak, M., & Boggs, J. W. (2010) · Xenobiotica · doi:10.3109/00498254.2010.514365 · Cited by 21

Inducible BRAF Suppression Models for Melanoma Tumorigenesis

Hoeflich, K. P., Jaiswal, B. S., Davis, D. P., & Seshagiri, S. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(07)00403-x · Cited by 11

Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas

Zhou, Y., Wang, J., Gu, Z., Wang, S., Zhu, W., Aceña, J. L., Soloshonok, V. A., Izawa, K., & Liu, H. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00392 · Cited by 2,843

Combined Vemurafenib and Cobimetinib in BRAF -Mutated Melanoma

Larkin, J., Ascierto, P. A., Dréno, B., Atkinson, V. G., Liszkay, G., Maio, M., Mandalà, M., Демидов, Л. В., Stroyakovskiy, D., Thomas, L., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408868 · Cited by 2,115

PI3K/AKT signaling pathway and cancer: an updated review

Martini, M., Santis, M. C. D., Braccini, L., Gulluni, F., & Hirsch, E. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.912836 · Cited by 1,195

RAS-targeted therapies: is the undruggable drugged?

Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103

The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma

Allen, E. M. V., Wagle, N., Sucker, A., Treacy, D. J., Johannessen, C. M., Goetz, E. M., Place, C. S., Taylor-Weiner, A. N., Whittaker, S. R., Kryukov, G. V., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0617 · Cited by 921

Abstract A250: Preclinical combination efficacy and identification of biomarkers of MEK and PI3K inhibitors in phase I

Hoeflich, K. P., Merchant, M. A., Otter, D. D., Chan, J., Chan, E. W., Orr, C., Friedman, L. S., Chan, I. T., Prescott, J., Berry, L., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.targ-09-a250 · Cited by 1

PK-PD modeling of combination efficacy effect from administration of the MEK inhibitor GDC-0973 and PI3K inhibitor GDC-0941 in A2058 xenografts

Choo, E. F., Ng, C. M., Berry, L., Belvin, M. P., Lewin‐Koh, N., Merchant, M. A., & Salphati, L. (2012) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-012-1988-6 · Cited by 30

Abstract 873: Combined targeting of Akt and MEK with the Akt inhibitor GDC-0068 and MEK inhibitor GDC-0973 demonstrates synergistic anti-tumor effects

Nannini, M., Hong, R., Lee, B. B., Arrazate, A., Kassees, R., Lin, J., Degtyarev, M. Y., Sampath, D., & Lin, K. (2012) · Cancer Research · doi:10.1158/1538-7445.am2012-873 · Cited by 2

The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition

Haagensen, E. J., Kyle, S., Beale, G., Maxwell, R. J., & Newell, D. R. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.70 · Cited by 80

Synergistic effects of multi-level targeting of the MAPK and PI3-kinase pathways in breast cancer cells.

Mirzoeva, O. K., Gendelman, R., Knight, Z. A., Neve, R. M., Feiler, H. S., Han, J., Kuo, W., Bayani, N., Siwak, D. R., Mills, G. B., et al. (2007) · Molecular Cancer Therapeutics