Reference Detail

Ref Type

Journal Article

PMID

(23629727)

Authors

Martinelli E, Troiani T, D'Aiuto E, Morgillo F, Vitagliano D, Capasso A, Costantino S, Ciuffreda LP, Merolla F, Vecchione L, De Vriendt V, Tejpar S, Nappi A, Sforza V, Martini G, Berrino L, De Palma R, Ciardiello F

Title

Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of cancer	133	9	2013 Nov	2089-101	Int J Cancer

URL

Abstract Text

The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti-cancer therapies. The in vitro and in vivo anti-tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi-targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib-sensitive (IC50 for cell growth inhibition of 0.001 µM) or pimasertib-resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up-regulated in pimasertib-resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK- and AKT-dependent signaling pathways in pimasertib-resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition.

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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	colorectal cancer	sensitive	Everolimus + Pimasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) and Afinitor (everolimus) synergistically inhibited proliferation of colorectal cancer cells harboring BRAF V600E in culture (PMID: 23629727).	23629727
NRAS Q61K	lung non-small cell carcinoma	sensitive	Pimasertib + Regorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) and Stivarga (regorafenib) synergistically inhibited proliferation of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 23629727).	23629727
BRAF V600E PIK3CA P449T	colorectal cancer	sensitive	Everolimus + Pimasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) and Afinitor (everolimus) synergistically inhibited proliferation of colorectal cancer cells harboring BRAF V600E and PIK3CA P449T in culture (PMID: 23629727).	23629727
NRAS Q61K	lung non-small cell carcinoma	sensitive	Everolimus + Pimasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) and Afinitor (everolimus) synergistically inhibited proliferation of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 23629727).	23629727
NRAS Q61K	lung non-small cell carcinoma	sensitive	Pimasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) inhibited proliferation of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 23629727).	23629727
BRAF V600E PIK3CA P449T	colorectal cancer	sensitive	Pimasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) inhibited proliferation of colorectal cancer cells harboring BRAF V600E and PIK3CA P449T in culture (PMID: 23629727).	23629727
NRAS Q61K	lung non-small cell carcinoma	sensitive	Pimasertib + Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) and Nexavar (sorafenib) synergistically inhibited proliferation of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 23629727).	23629727
BRAF V600E PIK3CA P449T	colorectal cancer	sensitive	Pimasertib + Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) and Nexavar (sorafenib) synergistically inhibited proliferation of colorectal cancer cells harboring BRAF V600E and PIK3CA P449T in culture (PMID: 23629727).	23629727
BRAF V600E PIK3CA P449T	colorectal cancer	sensitive	Pimasertib + Regorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) and Stivarga (regorafenib) synergistically inhibited proliferation of colorectal cancer cells harboring BRAF V600E and PIK3CA P449T in culture (PMID: 23629727).	23629727
BRAF V600E	colorectal cancer	sensitive	Pimasertib + Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) and Nexavar (sorafenib) synergistically inhibited proliferation of colorectal cancer cells harboring BRAF V600E in culture (PMID: 23629727).	23629727
BRAF V600E	colorectal cancer	sensitive	Pimasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) inhibited proliferation of colorectal cancer cells harboring BRAF V600E in culture (PMID: 23629727).	23629727
BRAF V600E	colorectal cancer	sensitive	Pimasertib + Regorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Pimasertib (MSC1936369B) and Stivarga (regorafenib) synergistically inhibited proliferation of colorectal cancer cells harboring BRAF V600E in culture (PMID: 23629727).	23629727