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|Ref Type||Journal Article|
|Authors||García-García C, Rivas MA, Ibrahim YH, Calvo MT, Gris-Oliver A, Rodríguez O, Grueso J, Antón P, Guzmán M, Aura C, Nuciforo P, Jessen K, Argilés G, Dienstmann R, Bertotti A, Trusolino L, Matito J, Vivancos A, Chicote I, Palmer HG, Tabernero J, Scaltriti M, Baselga J, Serra V|
|Title||MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by TP53 Mutation in Preclinical Models of Colorectal Cancer.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2015 Dec 15|
|Abstract Text||PI3K pathway activation occurs in concomitance with RAS/BRAF mutations in colorectal cancer, limiting the sensitivity to targeted therapies. Several clinical studies are being conducted to test the tolerability and clinical activity of dual MEK and PI3K pathway blockade in solid tumors.In the present study, we explored the efficacy of dual pathway blockade in colorectal cancer preclinical models harboring concomitant activation of the ERK and PI3K pathways. Moreover, we investigated if TP53 mutation affects the response to this therapy.Dual MEK and mTORC1/2 blockade resulted in synergistic antiproliferative effects in cell lines bearing alterations in KRAS/BRAF and PIK3CA/PTEN. Although the on-treatment cell-cycle effects were not affected by the TP53 status, a marked proapoptotic response to therapy was observed exclusively in wild-type TP53 colorectal cancer models. We further interrogated two independent panels of KRAS/BRAF- and PIK3CA/PTEN-altered cell line- and patient-derived tumor xenografts for the antitumor response toward this combination of agents. A combination response that resulted in substantial antitumor activity was exclusively observed among the wild-type TP53 models (two out of five, 40%), but there was no such response across the eight mutant TP53 models (0%). Interestingly, within a cohort of 14 patients with colorectal cancer treated with these agents for their metastatic disease, two patients with long-lasting responses (32 weeks) had TP53 wild-type tumors.Our data support that, in wild-type TP53 colorectal cancer cells with ERK and PI3K pathway alterations, MEK blockade results in potent p21 induction, preventing apoptosis to occur. In turn, mTORC1/2 inhibition blocks MEK inhibitor-mediated p21 induction, unleashing apoptosis. Clin Cancer Res; 21(24); 5499-510. ©2015 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|TP53 wild-type||colorectal cancer||predicted - sensitive||PD-0325901 + Sapanisertib||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, Sapanisertib (MLN0128) and PD-0325901 synergistically induced apoptosis in TP53 wild-type but not TP53 mutated colorectal cancer cell lines in culture, and demonstrated anti-tumor activity in TP53 wild-type but not TP53 mutated patient-derived xenograft models (PMID: 26272063).||26272063|
|BRAF V600E PTEN loss TP53 wild-type||colorectal cancer||sensitive||PD-0325901 + Sapanisertib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Sapanisertib (MLN0128) and PD-0325901 synergistically inhibited Erk and PI3K signaling and proliferation, induced apoptosis in TP53-wild-type colorectal cancer cells harboring BRAF V600E and PTEN loss in culture and in cell line xenograft models (PMID: 26272063).||26272063|
|BRAF V600E PIK3CA H1047R TP53 wild-type||colorectal cancer||sensitive||PD-0325901 + Sapanisertib||Preclinical - Cell culture||Actionable||In a preclinical study, Sapanisertib (MLN0128) and PD-0325901 synergistically inhibited Erk and PI3K signaling and proliferation, induced apoptosis in TP53-wild-type colorectal cancer cells harboring BRAF V600E and PIK3CA H1047R in culture (PMID: 26272063).||26272063|
|BRAF V600E PIK3CA P449T TP53 R273H||colorectal cancer||sensitive||PD-0325901 + Sapanisertib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Sapanisertib (MLN0128) and PD-0325901 synergistically inhibited Erk and PI3K signaling and growth of colorectal cancer cells harboring BRAF V600E, PIK3CA P449T, and TP53 R273H in culture and in cell line xenograft models, but did not have synergistic effect on apoptosis (PMID: 26272063).||26272063|