A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors
Open accessPublished version of a preprint
Abstract
Purpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non–small cell lung, ovarian, or pancreatic cancer. Results: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non–small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. Conclusions: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. Clin Cancer Res; 21(4); 730–8. ©2014 AACR.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Despite attempts to verify the efficacy of combined PI3K and MEK inhibition, no desirable clinical result has been achieved for mutant-RAS tumors, and none of the approved PI3K inhibitors is adapted to treat them.
“Despite attempts to verify the efficacy of combined inhibition of PI3K and MEK, no desirable clinical result has been achieved for mutant-RAS tumors, and none of the approved PI3K inhibitors is adapted to treat them.620–622”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [621]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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 · see citing works
Bendell, J. C., Rodon, J. A., Burris, H. A., de Jonge, M. J. A., Verweij, J., Birle, D. C., Demanse, D., Buck, S. S. D., Ru, Q. C., Peters, M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.36.1360 · Cited by 687 · see citing works
Self-citationAscierto, P. A., Schadendorf, D., Berking, C., Agarwala, S. S., van Herpen, C. M., Queirolo, P., Blank, C. U., Hauschild, A., Beck, J. T., St-Pierre, A., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70024-x · Cited by 640 · see citing works
Self-citationInfante, J. R., Fecher, L. A., Falchook, G. S., Nallapareddy, S., Gordon, M. S., Becerra, C., DeMarini, D. J., Cox, D. S., Xu, Y., Morris, S. R., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70270-x · Cited by 552 · see citing works
Self-citationFalchook, G. S., Lewis, K. D., Infante, J. R., Gordon, M. S., Vogelzang, N. J., DeMarini, D. J., Sun, P. G., Moy, C. H., Szabo, S. A., Roadcap, L., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70269-3 · Cited by 545 · see citing works
Self-citationIhle, N. T., Byers, L. A., Kim, E. S., Saintigny, P., Lee, J. J., Blumenschein, G. R., Tsao, A., Liu, S., Larsen, J. E., Wang, J., et al. (2012) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djr523 · Cited by 532 · see citing works
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 467 · see citing works
Critical aspects of the Bayesian approach to phase I cancer trials
Neuenschwander, B. E., Branson, M., & Gsponer, T. (2008) · Statistics in Medicine · doi:10.1002/sim.3230 · Cited by 443 · see citing works
Farley, J. H., Brady, W. E., Vathipadiekal, V., Lankes, H. A., Coleman, R. L., Morgan, M. A., Mannel, R. S., Yamada, S. D., Mutch, D. G., Rodgers, W. H., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70572-7 · Cited by 417 · see citing works
Tejpar, S., Celik, I., Schlichting, M., Sartorius, U., Bokemeyer, C., & Van Cutsem, E. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.42.2592 · Cited by 353 · see citing works
Jankú, F., Wheler, J. J., Naing, A., Falchook, G. S., Hong, D. S., Stepanek, V. M. T., Fu, S., Piha-Paul, S. A., Lee, J. J., Luthra, R., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1726 · Cited by 300 · see citing works
Biganzoli, E. M., Boracchi, P., Mariani, L., & Marubini, E. (1998) · Statistics in Medicine · doi:10.1002/(sici)1097-0258(19980530)17:10 · Cited by 274 · see citing works
Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer
Arrington, A. K., Heinrich, E. L., Lee, W., Duldulao, M., Patel, S., Sanchez, J., Garcia-Aguilar, J., & Kim, J. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131012153 · Cited by 244 · see citing works
PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types
Britten, C. D. (2013) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-013-2121-1 · Cited by 212 · see citing works
Self-citationDiscovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)
Abé, H., Kikuchi, S., Hayakawa, K., Iida, T., Nagahashi, N., Maeda, K., Sakamoto, J., Matsumoto, N., Miura, T., Matsumura, K., et al. (2011) · ACS Medicinal Chemistry Letters · doi:10.1021/ml200004g · Cited by 202 · see citing works
KRAS and BRAF: drug targets and predictive biomarkers
Vakiani, E., & Solit, D. B. (2010) · The Journal of Pathology · doi:10.1002/path.2796 · Cited by 158 · see citing works
Identification of JTP‐70902, a p15INK4b‐inductive compound, as a novel MEK1/2 inhibitor
Yamaguchi, T., Yoshida, T., Kurachi, R., Kakegawa, J., Hori, Y., Nanayama, T., Hayakawa, K., Abe, H., Takagi, K., Matsuzaki, Y., et al. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00604.x · Cited by 54 · see citing works
Baselga, J. M., Jonge, M. J. D., Rodon, J. A., Burris, H. A., Birle, D. C., Buck, S. S. D., Demanse, D., Ru, Q. C., Goldbrunner, M., & Bendell, J. C. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.15_suppl.3003 · Cited by 53 · see citing works
Self-citationKullmann, F., Hartmann, A., Stöhr, R., Messmann, H., Dollinger, M. M., Trojan, J., Fuchs, M., Hollerbach, S., Harder, J., Troppmann, M., et al. (2011) · Oncology · doi:10.1159/000330194 · Cited by 46 · see citing works
Shapiro, G. I., LoRusso, P. M., Kwak, E. L., Cleary, J. M., Musib, L. C., Jones, C. B., de Crespigny, A. J., Belvin, M. P., McKenzie, M., Gates, M. R., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.15_suppl.3005 · Cited by 44 · see citing works
Tolcher, A. W., Baird, R. D., Patnaik, A., Garcia, V. M., Papadopoulos, K. P., Garrett, C. R., Olmos, D., Shannon, K., Zazulina, V., Rubin, E. H., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.15_suppl.3004 · Cited by 35 · see citing works
K-Ras Mutations in Non-Small-Cell Lung Cancer: Prognostic and Predictive Value
D’Arcangelo, M., & Cappuzzo, F. (2012) · ISRN Molecular Biology · doi:10.5402/2012/837306 · Cited by 31 · see citing works
Hannigan, A., Qureshi, M. A., Nixon, C., Tsimbouri, P. M., Jones, S., Philbey, A., & Wilson, J. B. (2011) · Molecular Cancer · doi:10.1186/1476-4598-10-11 · Cited by 30 · see citing works
Kurzrock, R., Patnaik, A., Rosenstein, L., Fu, S. W., Papadopoulos, K. P., Smith, D. A., Falchook, G. S., Chambers, G., Gauvin, J., Naing, A., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.15_suppl.3085 · Cited by 28 · see citing works
Self-citationModest, D. P., Brodowicz, T., Stintzing, S., Jung, A., Neumann, J. H. L., Laubender, R. P., Ocvirk, J., Kurteva, G. P., Pápai, Z., Knittelfelder, R., et al. (2012) · Oncology · doi:10.1159/000339534 · Cited by 27 · see citing works
Infante, J. R., Gandi, L., Shapiro, G. I., Rizvi, N. A., Burris, H. A., Bendell, J. C., Baselga, J. M., Hsu, K., von Richter, O., Locatelli, G., et al. (2013) · Cancer Research · doi:10.1158/1538-7445.am2013-lb-147 · Cited by 18 · see citing works
Activation of the MEK–S6 Pathway in High-grade Ovarian Cancers
Ventura, A. P., Radhakrishnan, S. V., Green, A. F., Rajaram, S. K., Allen, A. N., O'Briant, K. C., Schummer, M., Karlan, B. Y., Urban, N. D., Tewari, M., et al. (2010) · Applied immunohistochemistry & molecular morphology · doi:10.1097/pai.0b013e3181e53e1c · Cited by 14 · see citing works
Britten, C. D., Wainberg, Z. A., Tabernero, J. M., Alsina, M., Leong, S., Sessa, C., Millham, R., Gallo, J. D., Siu, L. L., & Braña, I. (2012) · European Journal of Cancer · doi:10.1016/s0959-8049(12)72156-1 · Cited by 10 · see citing works
Self-citationGrilley‐Olson, J. E., Bedard, P., Fasolo, A., Blackman, S. C., Cartee, L., Baker-Neblett, K. L., Sun, P. G., & Infante, J. R. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.targ-11-b155 · Cited by 2 · see citing works
Self-citationPress, M. F., Gordon, M. A., & Slamon, D. J. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.35.1023 · Cited by 2 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- [15]15. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: ef fi cient dose escalation with overdose control. Stat Med 1998;17:1103 -20.
- [24]24. Janku F, Wheler JJ, Naing A, Falchook GS, Hong DS, Stepanek VM, et al. PIK3CAmutationH1047RisassociatedwithresponsetoPI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res 2013;73:276 -84.
- [28]28. Tejpar S, Celik I, Schlichting M, Sartorius U, Bokemeyer C, Van Cutsem E. Association of KRAS G13Dtumormutationswithoutcomeinpatientswith metastatic colorectal cancer treated with fi rst-line chemotherapy with or without cetuximab. J Clin Oncol 2012;30:357 -07.
Cited by
Sorted by citations
Targeting PI3K/Akt signal transduction for cancer therapy
He, Y., Sun, M., Zhang, G. G., Yang, J., Chen, K. S., Xu, W. W., & Li, B. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00828-5 · Cited by 1,996 · see citing works
Targeting PI3K in cancer: mechanisms and advances in clinical trials
Yang, J., Nie, J., Ma, X., Wei, Y., Peng, Y., & Wei, X. (2019) · Molecular Cancer · doi:10.1186/s12943-019-0954-x · Cited by 1,538 · see citing works
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 · see citing works
Targeting the PI3K pathway in cancer: are we making headway?
Janku, F., Yap, T. A., & Meric-Bernstam, F. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.28 · Cited by 1,033 · see citing works
Development of PI3K inhibitors: lessons learned from early clinical trials
Rodon, J. A., Dienstmann, R., Serra, V., & Tabernero, J. M. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.10 · Cited by 770 · see citing works
Self-citationEdiriweera, M. K., Tennekoon, K. H., & Samarakoon, S. R. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.05.012 · Cited by 752 · see citing works
MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
Caunt, C. J., Sale, M. J., Smith, P. D., & Cook, S. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4000 · Cited by 606 · see citing works
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527 · see citing works
YAP/TAZ Signaling and Resistance to Cancer Therapy
Nguyen, C. D. K., & Yi, C. (2019) · Trends in Cancer · doi:10.1016/j.trecan.2019.02.010 · Cited by 437 · see citing works
Therapeutic strategies to target RAS-mutant cancers
Ryan, M. B., & Corcoran, R. B. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0105-0 · Cited by 420 · see citing works
Combine and conquer: challenges for targeted therapy combinations in early phase trials
Lopez, J. S., & Banerji, U. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.96 · Cited by 394 · see citing works
Obesity and Cancer Mechanisms: Cancer Metabolism
Hopkins, B. D., Goncalves, M. D., & Cantley, L. C. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.67.9712 · Cited by 415 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments
Yip, H. Y. K., & Papa, A. (2021) · Cells · doi:10.3390/cells10030659 · Cited by 332 · see citing works
PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects
Mishra, R., Patel, H. M., Alanazi, S., Kilroy, M. K., & Garrett, J. T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073464 · Cited by 293 · see citing works
Lehmann, B. D., Colaprico, A., Silva, T. C., Chen, J., An, H., Ban, Y. J., Huang, H., Wang, L. H.-C., James, J. L., Balko, J. M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26502-6 · Cited by 283 · see citing works
Zhao, H., Wang, J., Shao, W., Wu, C.-P., Chen, Z.-P., To, S.-S. T., & Li, W.-P. (2017) · Molecular Cancer · doi:10.1186/s12943-017-0670-3 · Cited by 255 · see citing works
Tsimberidou, A. M. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2861-1 · Cited by 255 · see citing works
Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients
Jankú, F. (2017) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2017.07.005 · Cited by 245 · see citing works
Emerging strategies to target RAS signaling in human cancer therapy
Chen, K., Zhang, Y., Qian, L. M., & Wang, P. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01127-w · Cited by 231 · see citing works
Chemoresistance and targeted therapies in ovarian and endometrial cancers
Brasseur, K., Gévry, N. Y., & Asselin, É. (2016) · Oncotarget · doi:10.18632/oncotarget.14021 · Cited by 224 · see citing works
PIK3CA in cancer: The past 30 years
Arafeh, R., & Samuels, Y. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.02.002 · Cited by 215 · see citing works
Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies
Chiorean, E. G., & Coveler, A. L. (2015) · Drug Design Development and Therapy · doi:10.2147/dddt.s60328 · Cited by 214 · see citing works
Yu, X., Long, Y. C., & Shen, H. (2015) · Autophagy · doi:10.1080/15548627.2015.1043076 · Cited by 205 · see citing works
Drugging PI3K in cancer: refining targets and therapeutic strategies
Yap, T. A., Bjerke, L. M., Clarke, P. A., & Workman, P. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.05.016 · Cited by 204 · see citing works
PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment
Leiphrakpam, P., & Are, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063178 · Cited by 193 · see citing works
KRAS-related proteins in pancreatic cancer
Mann, K. M., Ying, H., Juan, J. M., Jenkins, N. A., & Copeland, N. G. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.09.003 · Cited by 186 · see citing works
MEK inhibitor resistance mechanisms and recent developments in combination trials
Kun, E., Tsang, Y. T. M., Ng, C. W., Gershenson, D. M., & Wong, K. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.102137 · Cited by 189 · see citing works
Kabacaoğlu, D., Ciecielski, K. J., Ruess, D. A., & Algül, H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01878 · Cited by 175 · see citing works
Trametinib: a MEK inhibitor for management of metastatic melanoma
Rutkowski, P. L., Ługowska, I., Koseła-Paterczyk, H., & Kozak, K. (2015) · OncoTargets and Therapy · doi:10.2147/ott.s72951 · Cited by 171 · see citing works
A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma
Krepler, C., Sproesser, K., Brafford, P. A., Beqiri, M., Garman, B., Xiao, M., Shannan, B., Watters, A. K., Perego, M., Zhang, G., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.021 · Cited by 151 · see citing works
Monk, B. J., Grisham, R. N., Banerjee, S. N., Kalbacher, E., Mirza, M. R., Romero, I., Vuylsteke, P., Coleman, R. L., Hilpert, F., Oza, A. M., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.20.01164 · Cited by 158 · see citing works
Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence
Wang, Q., Peng, H., Qi, X., Wu, M., & Zhao, X. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0199-6 · Cited by 157 · see citing works
Dreyling, M. H., Santoro, A., Mollica, L. R., Leppä, S., Follows, G., Lenz, G., Kim, W. S., Nagler, A., Dimou, M., Demeter, J., et al. (2019) · American Journal of Hematology · doi:10.1002/ajh.25711 · Cited by 156 · see citing works
PI3K/AKT/mTOR Axis in Cancer: From Pathogenesis to Treatment
Jiang, M., Zhang, K., Zhang, Z., Zeng, X., Huang, Z., Qin, P., Xie, Z., Cai, X., Ashrafizadeh, M., Tian, Y., et al. (2025) · MedComm · doi:10.1002/mco2.70295 · Cited by 173 · see citing works
Targeting PI3K Signaling in Combination Cancer Therapy
Tostivint, E. P., Thibault, B., & Guillermet‐Guibert, J. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.04.002 · Cited by 141 · see citing works
Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects
Stanciu, S., Radu, F. I., Ștefani, C., Miricescu, D., Stănescu-Spînu, I.-I., Greabu, M., Totan, A., & Jinga, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231710132 · Cited by 144 · see citing works
Sai, J., Owens, P., Novitskiy, S. V., Hawkins, O. E., Vilgelm, A. E., Yang, J., Sobolik, T., Lavender, N., Johnson, A. C., McClain, C., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2142 · Cited by 138 · see citing works
Targeting RAS-mutant cancers: is ERK the key?
Ryan, M. B., Der, C., Wang-Gillam, A., & Cox, A. (2015) · Trends in Cancer · doi:10.1016/j.trecan.2015.10.001 · Cited by 125 · see citing works
Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
Rusan, M., Li, K., Li, Y. Y., Christensen, C. L., Abraham, B. J., Kwiatkowski, N. P., Buczkowski, K. A., Bockorny, B., Chen, T., Li, S., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0461 · Cited by 128 · see citing works
Genomic alterations in thyroid cancer: biological and clinical insights
Landa, I., & Cabanillas, M. E. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00920-6 · Cited by 134 · see citing works
MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival
Lee, C.-S., Lee, L. C., Yuan, T. L., Chakka, S., Fellmann, C., Lowe, S. W., Caplen, N. J., McCormick, F., & Luo, J. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1817494116 · Cited by 126 · see citing works
The Complexity of the ERK/MAP-Kinase Pathway and the Treatment of Melanoma Skin Cancer
Wellbrock, C., & Arozarena, I. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00033 · Cited by 126 · see citing works
Overcoming resistance to BRAF inhibitors
Arozarena, I., & Wellbrock, C. (2017) · Annals of Translational Medicine · doi:10.21037/atm.2017.06.09 · Cited by 125 · see citing works
MEK and PI3K inhibition in solid tumors: rationale and evidence to date
Jokinen, E., & Koivunen, J. P. (2015) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834015571111 · Cited by 116 · see citing works
A microfluidic assay for the quantification of the metastatic propensity of breast cancer specimens
Yankaskas, C. L., Thompson, K. N., Paul, C. D., Vitolo, M. I., Mistriotis, P., Mahendra, A., Bajpai, V. K., Shea, D. J., Manto, K. M., Chai, A. C., et al. (2019) · Nature Biomedical Engineering · doi:10.1038/s41551-019-0400-9 · Cited by 113 · see citing works
Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors
Philip, C., Laskov, I., Beauchamp, M.-C., Marques, M., Amin, O., Bitharas, J., Kessous, R., Kogan, L., Baloch, T., Gotlieb, W. H., et al. (2017) · BMC Cancer · doi:10.1186/s12885-017-3639-0 · Cited by 115 · see citing works
Brown, W. S., McDonald, P. C., Nemirovsky, O., Awrey, S., Chafe, S. C., Schaeffer, D. F., Li, J., Renouf, D. J., Stanger, B. Z., & Dedhar, S. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100131 · Cited by 111 · see citing works
Cell Type–Specific Adaptive Signaling Responses to KRASG12C Inhibition
Solanki, H. S., Welsh, E. A., Fang, B., Izumi, V., Darville, L., Stone, B., Franzese, R., Chavan, S., Kinose, F., Imbody, D., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3872 · Cited by 106 · see citing works
Advances in Ovarian Cancer Treatment Beyond PARP Inhibitors
Aliyuda, F., Moschetta, M., Ghose, A., Rallis, K. S., Sheriff, M., Sanchez, E., Rassy, E., & Boussios, S. (2023) · Current Cancer Drug Targets · doi:10.2174/1568009623666230209121732 · Cited by 103 · see citing works
Li, H., Wen, X., Ren, Y., Fan, Z., Zhang, J., He, G., & Fu, L. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02072-1 · Cited by 110 · see citing works
Wang, D., Li, C., Zhang, Y., Wang, M., Jiang, N., Lin, X., Li, T., Roberts, T. M., Zhao, J. J., Cheng, H.-L. M., et al. (2016) · Gynecologic Oncology · doi:10.1016/j.ygyno.2016.07.092 · Cited by 100 · see citing works
Wainberg, Z. A., Alsina, M., Soares, H. P., Braña, I., Britten, C. D., Del Conte, G., Ezeh, P., Houk, B., Kern, K. A., Leong, S., et al. (2017) · Targeted Oncology · doi:10.1007/s11523-017-0530-5 · Cited by 98 · see citing works
Self-citationSchram, A. M., Gandhi, L., Mita, M. M., Damstrup, L., Campana, F., Hidalgo, M., Grande, E., Hyman, D. M., & Heist, R. S. (2018) · British Journal of Cancer · doi:10.1038/s41416-018-0322-4 · Cited by 96 · see citing works
Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine
Conway, J. R. W., Herrmann, D., Evans, T. J., Morton, J. P., & Timpson, P. (2018) · Gut · doi:10.1136/gutjnl-2018-316822 · Cited by 93 · see citing works
Nangia, V., Siddiqui, F. M., Caenepeel, S., Timonina, D., Bilton, S. J., Phan, N., Gomez-Caraballo, M., Archibald, H. L., Li, C., Fraser, C., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0277 · Cited by 94 · see citing works
Approaches to modernize the combination drug development paradigm
Day, D., & Siu, L. L. (2016) · Genome Medicine · doi:10.1186/s13073-016-0369-x · Cited by 94 · see citing works
MAPK pathway in melanoma part II—secondary and adaptive resistance mechanisms to BRAF inhibition
Amaral, T. M. S., Sinnberg, T. W., Meier, F. E., Krepler, C., Levesque, M. P., Niessner, H., & Garbe, C. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2016.12.012 · Cited by 93 · see citing works
Mossenta, M., Busato, D., Bo, M. D., & Toffoli, G. (2020) · Cancers · doi:10.3390/cancers12061668 · Cited by 90 · see citing works
Shapiro, G. I., LoRusso, P., Kwak, E., Pandya, S., Rudin, C. M., Kurkjian, C., Cleary, J. M., Pilat, M. J., Jones, S., de Crespigny, A., et al. (2020) · Investigational New Drugs · doi:10.1007/s10637-019-00776-6 · Cited by 90 · see citing works
Rinne, N., Christie, E. L., Ardasheva, A., Kwok, C. H., Demchenko, N., Low, C. M. R., Tralau, C. J., Fotopoulou, C., & Cunnea, P. (2021) · Cancer Drug Resistance · doi:10.20517/cdr.2021.05 · Cited by 88 · see citing works
Strategies to tackle RAS-mutated metastatic colorectal cancer
Patelli, G., Tosi, F., Amatu, A., Mauri, G., Curaba, A., Patanè, D. A., Pani, A., Scaglione, F., Siena, S., & Sartore-Bianchi, A. (2021) · ESMO Open · doi:10.1016/j.esmoop.2021.100156 · Cited by 86 · see citing works
Bardia, A., Gounder, M., Rodón, J., Janku, F., Lolkema, M., Stephenson, J., Bédard, P., Schuler, M., Sessa, C., LoRusso, P., et al. (2019) · The Oncologist · doi:10.1634/theoncologist.2019-0297 · Cited by 79 · see citing works
Self-citationPathogenesis of cancers derived from thyroid follicular cells
Fagin, J. A., Krishnamoorthy, G. P., & Landa, I. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00598-y · Cited by 86 · see citing works
Li, Y., Umbach, D. M., Krahn, J. M., Shats, I., Li, X., & Li, L. (2021) · BMC Genomics · doi:10.1186/s12864-021-07581-7 · Cited by 84 · see citing works
Grilley-Olson, J. E., Bedard, P. L., Fasolo, A., Cornfeld, M., Cartee, L., Razak, A. R. A., Stayner, L.-A., Wu, Y., Greenwood, R., Singh, R., et al. (2016) · Investigational New Drugs · doi:10.1007/s10637-016-0377-0 · Cited by 81 · see citing works
Self-citationTargeted therapies in development for non-small cell lung cancer
Dy, G. K., & Reungwetwattana, T. (2013) · Journal of Carcinogenesis · doi:10.4103/1477-3163.123972 · Cited by 80 · see citing works
Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
Tang, D., Kroemer, G., & Kang, R. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01422-7 · Cited by 80 · see citing works
Takeda, M., Sakai, K., Terashima, M., Kaneda, H., Hayashi, H., Tanaka, K., Okamoto, K., Takahama, T., Yoshida, T., Iwasa, T., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv475 · Cited by 80 · see citing works
Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade
Shin, M. H., Kim, J., Lim, S. A., Kim, J., & Lee, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072531 · Cited by 81 · see citing works
Targeted Therapy and Immunosuppression in the Tumor Microenvironment
Allegrezza, M. J., & Conejo-Garcia, J. R. (2016) · Trends in cancer · doi:10.1016/j.trecan.2016.11.009 · Cited by 79 · see citing works
Guo, C., Chénard-Poirier, M., Roda, D., de Miguel, M., Harris, S. J., Candilejo, I. M., Sriskandarajah, P., Xu, W., Scaranti, M., Constantinidou, A., et al. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(20)30464-2 · Cited by 78 · see citing works
Kalli, M., Minia, A., Pliaka, V., Fotis, C., Alexopoulos, L. G., & Stylianopoulos, T. (2019) · Scientific Reports · doi:10.1038/s41598-018-37425-6 · Cited by 78 · see citing works
Hendrikse, C. S. E., Theelen, P. M. M., van der Ploeg, P., Westgeest, H. M., Boere, I. A., Thijs, A. M. J., Ottevanger, P. B., van de Stolpe, A., Lambrechts, S., Bekkers, R. L. M., et al. (2023) · Gynecologic Oncology · doi:10.1016/j.ygyno.2023.01.038 · Cited by 75 · see citing works
Hata, A. N., Yeo, A., Faber, A. C., Lifshits, E., Chen, Z., Cheng, K. A., Walton, Z., Sarosiek, K. A., Letai, A., Heist, R. S., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3728 · Cited by 74 · see citing works
MEK inhibitors under development for treatment of non-small-cell lung cancer
Kim, C. G., & Giaccone, G. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2018.1415324 · Cited by 73 · see citing works
Leroux, C., & Konstantinidou, G. (2021) · Cancers · doi:10.3390/cancers13040799 · Cited by 76 · see citing works
Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter
Qiu, J.-G., Zhang, Y., Li, Y., Zhao, J., Zhang, W., Jiang, Q., Mei, X.-L., Xue, Y., Qin, W.-M., Yang, Y., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3820 · Cited by 68 · see citing works
Algazi, A., Esteve-Puig, R., Nosrati, A., Hinds, B., Hobbs‐Muthukumar, A., Nandoskar, P., Ortiz-Urda, S., Chapman, P., & Daud, A. (2017) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12644 · Cited by 59 · see citing works
YY1 regulates melanoma tumorigenesis through a miR-9 ~ RYBP axis
Zhao, G., Li, Q., Wang, A., & Jiao, J. (2015) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-015-0177-y · Cited by 66 · see citing works
SIRT6, a novel direct transcriptional target of FoxO3a, mediates colon cancer therapy
Zhang, Y., Nie, L., Xu, K., Fu, Y., Zhong, J., Gu, K., & Zhang, L. (2019) · Theranostics · doi:10.7150/thno.29724 · Cited by 67 · see citing works
The Therapeutic Potential of MAPK/ERK Inhibitors in the Treatment of Colorectal Cancer
Pashirzad, M., Khorasanian, R., Fard, M. M., Arjmand, M., Langari, H., Khazaei, M., Soleimanpour, S., Rezayi, M., Ferns, G. A., Hassanian, S. M., et al. (2021) · Current Cancer Drug Targets · doi:10.2174/1568009621666211103113339 · Cited by 64 · see citing works
Chaudagar, K. K., Hieromnimon, H. M., Kelley, A., Labadie, B. W., Shafran, J. S., Rameshbabu, S., Drovetsky, C., Bynoe, K. M., Solanki, A., Markiewicz, E. J., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-1441 · Cited by 66 · see citing works
Silva, A. P. S., Coelho, P. V., Anazetti, M. C., & Simioni, P. U. (2016) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2016.1249551 · Cited by 62 · see citing works
Zhou, Y., Liu, W., Xu, Z., Zhu, H., Xiao, D., Su, W., Zeng, R., Feng, Y., Duan, Y., Zhou, J., et al. (2018) · Neoplasia · doi:10.1016/j.neo.2018.08.012 · Cited by 60 · see citing works
Middleton, G., Robbins, H. L., André, F., & Swanton, C. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.11.004 · Cited by 58 · see citing works
Tolcher, A. W., Kurzrock, R., Valero, V., Gonzalez, R. C., Heist, R. S., Tan, A. R., Means-Powell, J. A., Werner, T. L., Becerra, C. R., Wang, C., et al. (2020) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-020-04038-8 · Cited by 59 · see citing works
Boespflug, A. M., Caramel, J., Dalle, S., & Thomas, L. (2017) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834017708160 · Cited by 57 · see citing works
Mutant HRAS as novel target for MEK and mTOR inhibitors
Kiessling, M., Curioni-Fontecedro, A., Samaras, P., Atrott, K., Cosin-Roger, J., Lang, S., Scharl, M., & Rogler, G. (2015) · OncoTarget · doi:10.18632/oncotarget.5619 · Cited by 57 · see citing works
Molecular-targeted therapies and precision medicine for endometrial cancer
Mitamura, T., Dong, P., Ihira, K., 工藤, 正., & Watari, H. (2018) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyy159 · Cited by 56 · see citing works
KRAS: A Druggable Target in Colon Cancer Patients
Negri, F., Bottarelli, L., de’Angelis, G. L., & Gnetti, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084120 · Cited by 55 · see citing works
Therapeutic strategies of different HPV status in Head and Neck Squamous Cell Carcinoma
Sun, Y., Wang, Z., Qiu, S., & Wang, R. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.58077 · Cited by 54 · see citing works
Ramanathan, R. K., Hoff, D. D. V., Eskens, F. A. L. M., Blumenschein, G. R., Richards, D., Genvresse, I., Reschke, S., Granvil, C. P., Skubala, A., Peña, C. E., et al. (2020) · Targeted Oncology · doi:10.1007/s11523-020-00714-0 · Cited by 54 · see citing works
Cellular Mechanism of Gene Mutations and Potential Therapeutic Targets in Ovarian Cancer
Guo, T., Dong, X., Xie, S., Zhang, L., Zeng, P., & Zhang, L. (2021) · Cancer Management and Research · doi:10.2147/cmar.s292992 · Cited by 54 · see citing works
Targeting BRAF pathway in low-grade serous ovarian cancer
Perrone, C., Angioli, R., Luvero, D., Giannini, A., Donato, V. D., Cuccu, I., Muzii, L., Raspagliesi, F., & Bogani, G. (2024) · Journal of Gynecologic Oncology · doi:10.3802/jgo.2024.35.e104 · Cited by 55 · see citing works
Targeting of MEK in lung cancer therapeutics
Heigener, D. F., Gandara, D. R., & Reck, M. (2015) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(15)00026-0 · Cited by 53 · see citing works
Parkin, A., Man, J., Timpson, P., & Pajic, M. (2019) · FEBS Journal · doi:10.1111/febs.15011 · Cited by 52 · see citing works
KRAS: Reasons for optimism in lung cancer
Lindsay, C. R., Jamal‐Hanjani, M., Forster, M. D., & Blackhall, F. H. (2018) · European Journal of Cancer · doi:10.1016/j.ejca.2018.05.001 · Cited by 52 · see citing works
Vetter, M. H., & Hays, J. L. (2018) · Clinical Therapeutics · doi:10.1016/j.clinthera.2018.01.012 · Cited by 50 · see citing works
PI3K inhibition in breast cancer: Identifying and overcoming different flavors of resistance
Vitale, S. R., Martorana, F., Stella, S., Motta, G., Inzerilli, N., Massimino, M., Tirrò, E., Manzella, L., & Vigneri, P. G. (2021) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2021.103334 · Cited by 47 · see citing works
- Authors
- Bedard, P. L., Tabernero, J., Janku, F., Wainberg, Z. A., Paz-Ares, L., Vansteenkiste, J., Van Cutsem, E., Pérez-García, J., Stathis, A., Britten, C. D., Le, N., Carter, K., Demanse, D., Csonka, D., Peters, M., Zubel, A., Nauwelaerts, H., & Sessa, C.
- Affiliations
- Princess Margaret Cancer Centre (CA)
- Universitat Autònoma de Barcelona (ES)
- 3The University of Texas MD Anderson Cancer Center, Houston, Texas.
- University of California, Los Angeles (US)
- Hospital Universitario Virgen del Rocío (ES)
- Universitair Ziekenhuis Leuven (BE)
- 7Digestive Oncology, University Hospital KU Leuven, Leuven, Belgium.
- Istituto Oncologico della Svizzera Italiana (CH)
- GlaxoSmithKline (United States) (US)
- Novartis (Switzerland) (CH)
- 10Novartis Pharma AG, Basel, Switzerland.
- Corresponding author
- Sessa, Cristiana
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2015-02-15
- Volume
- 21
- Issue
- 4
- Pages
- 730-738
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W1988878042
- Cited by
- 324
- References
- 30
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 23 · 2023: 25 · 2022: 22 · 2021: 50 · 2020: 32 · 2019: 39 · 2018: 27 · 2017: 29 · 2016: 25 · 2015: 20 · 2014: 1 · 2013: 2
- FWCI
- 10.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Funders
- GlaxoSmithKline
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- buparlisib, trametinib, PI3K/AKT/mTOR inhibition, MEK1/2 inhibition, MAPK signaling, combination therapy, dose-limiting toxicity, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, ovarian cancer, non-small cell lung cancer, pancreatic cancer, stomatitis
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aminopyridines, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Morpholines, Neoplasms, Pyridones, Pyrimidinones, Disease-Free Survival, Maximum Tolerated Dose
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
