Reference SummaryRoberts PJ, Clin Cancer Res 2012 Oct 1;18(19):5290-303

Title

Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models.

Authors

Roberts PJ; Usary JE; Darr DB; Dillon PM; Pfefferle AD; Whittle MC; Duncan JS; Johnson SM; Combest AJ; Jin J; Zamboni WC; Johnson GL; Perou CM; Sharpless NE

Journal

Clin Cancer Res

Volume

Issue

Year

2012

Pages

5290-303

Abstract

PURPOSE: Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to in vitro and xenograft systems. EXPERIMENTAL DESIGN: We assessed the activity of 16 treatment regimens in a RAS-driven, Ink4a/Arf-deficient melanoma GEMM. In addition, we tested a subset of treatment regimens in three breast cancer models representing distinct breast cancer subtypes: claudin-low (T11 OST), basal-like (C3-TAg GEMM), and luminal B (MMTV-Neu GEMM). RESULTS: Like human RAS-mutant melanoma, the melanoma GEMM was refractory to chemotherapy and single-agent small molecule therapies. Combined treatment with AZD6244 [mitogen-activated protein-extracellular signal-regulated kinase kinase (MEK) inhibitor] and BEZ235 [dual phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor] was the only treatment regimen to exhibit significant antitumor activity, showed by marked tumor regression and improved survival. Given the surprising activity of the "AZD/BEZ" combination in the melanoma GEMM, we next tested this regimen in the "claudin-low" breast cancer model that shares gene expression features with melanoma. The AZD/BEZ regimen also exhibited significant activity in this model, leading us to testing in even more diverse GEMMs of basal-like and luminal breast cancer. The AZD/BEZ combination was highly active in these distinct breast cancer models, showing equal or greater efficacy compared with any other regimen tested in studies of over 700 tumor-bearing mice. This regimen even exhibited activity in lapatinib-resistant HER2(+) tumors. CONCLUSION: These results show the use of credentialed murine models for large-scale efficacy testing of diverse anticancer regimens and predict that combinations of PI3K/mTOR and MEK inhibitors will show antitumor activity in a wide range of human malignancies.

Links

J:234392 – MGI References
22872574 – National Library of Medicine/PubMed

Strain Notes

Strain	Note
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	By breeding male mice carrying the transgene and homozygous for the Cdkn2a knockout allele to female mice homozygous for the Cdkn2a knockout allele no genotyping of the progeny is necessary. "The males develop tumors and the females are used for future breeding."

Models
Strain	Model Name	Treatment Agent(s)	Organ Affected	Frequency
FVB-Tg(C3-1-TAg)cJeg	Mammary gland tumor - basal-like		Mammary gland	observed
FVB-Tg(C3-1-TAg)cJeg	Mammary gland tumor - basal-like	carboplatin Taxol (paclitaxel)	Mammary gland	observed
FVB-Tg(C3-1-TAg)cJeg	Mammary gland tumor - basal-like	sunitinib	Mammary gland	observed
FVB-Tg(C3-1-TAg)cJeg	Mammary gland tumor - basal-like	selumetinib (AZD6244)	Mammary gland	observed
FVB-Tg(C3-1-TAg)cJeg	Mammary gland tumor - basal-like	BEZ235 (NVP-BEZ235-AN)	Mammary gland	observed
FVB-Tg(C3-1-TAg)cJeg	Mammary gland tumor - basal-like	selumetinib (AZD6244) BEZ235 (NVP-BEZ235-AN)	Mammary gland	observed
B6;FVB-Tg(C3-1-TAg)cJeg	Mammary gland tumor - basal-like		Mammary gland	observed
FVB-Tg(MMTV-Erbb2)NK1Mul	Mammary gland tumor - luminal		Mammary gland	observed
FVB-Tg(MMTV-Erbb2)NK1Mul	Mammary gland tumor - luminal	carboplatin Taxol (paclitaxel)	Mammary gland	observed
FVB-Tg(MMTV-Erbb2)NK1Mul	Mammary gland tumor - luminal	lapatinib	Mammary gland	observed
FVB-Tg(MMTV-Erbb2)NK1Mul	Mammary gland tumor - luminal	selumetinib (AZD6244)	Mammary gland	observed
FVB-Tg(MMTV-Erbb2)NK1Mul	Mammary gland tumor - luminal	BEZ235 (NVP-BEZ235-AN)	Mammary gland	observed
FVB-Tg(MMTV-Erbb2)NK1Mul	Mammary gland tumor - luminal	selumetinib (AZD6244) BEZ235 (NVP-BEZ235-AN)	Mammary gland	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma		Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	ionizing radiation	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	lonafarnib	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	carboplatin	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	Taxol (paclitaxel)	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	carboplatin Taxol (paclitaxel)	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	veliparib (ABT-888)	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	veliparib (ABT-888) carboplatin	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	temozolomide (TMZ)	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	veliparib (ABT-888) temozolomide (TMZ)	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	erlotinib	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	lapatinib	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	sunitinib	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	salirasib (farnesylthiosalicylic acid) (FTS)	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	selumetinib (AZD6244)	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	BEZ235 (NVP-BEZ235-AN)	Skin - Melanocyte	observed
STOCK Cdkn2a^tm1Rdp Tg(Tyr-HRAS)60Lc	Skin - Melanocyte melanoma	selumetinib (AZD6244) BEZ235 (NVP-BEZ235-AN)	Skin - Melanocyte	observed