Reference Detail

Ref Type

Journal Article

PMID

(26272063)

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	21	24	2015 Dec 15	5499-5510	Clin Cancer Res

URL

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.

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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
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
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
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 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