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Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in KrasG12D-LSL mice

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Abstract

The role of PI3K and MAPK pathways in tumor initiation and progression is well established; hence, several inhibitors of these pathways are currently in different stages of clinical trials. Recent studies identified a PI3K/mTOR (PF-04691502) and a MEK inhibitor (PD-0325901) with strong potency and efficacy in different cell lines and tumor models. PD-0325901, however, showed adverse effects when administered at or above MTD (maximum tolerated dose) in the clinic. Here, we show in preclinical models that PD-0325901 at doses well below MTD (sub-MTD 1.5 mg/kg SID) is still a potent compound as single agent or in combination with PF-04691502. We first observed that PD-0325901 at 1.5 mg/kg SID and in combination with PF-04691502 (7.5 mg/kg; SID) significantly inhibited growth of H460 (carry Kras and PIK3CA mutations) orthotopic lung tumors. Additionally, we tested efficacy of PD-0325901 in KrasG12D-LSL conditional GEMMs (genetically engineered mouse models) which are a valuable tool in translational research to study tumor progression. Intranasal delivery of adenoviruses expressing Cre recombinase (Adeno-Cre) resulted in expression of mutant Kras leading to development of tumor lesions in lungs including adenomatous hyperplasia, large adenoma, and adenocarcinoma. Similar to H460 tumors, PD-0325901 as single agent or in combination with PF-04691502 significantly inhibited growth of tumor lesions in lungs in KrasG12D-LSL mice when treatment started at adenocarcinoma stage (at 14 weeks post-Adeno-Cre inhalation). In addition, immunohistochemistry showed inhibition of pS6 (phosphorylated ribosomal S6) in the treated animals particularly in the combination group providing a proof of mechanism for tumor growth inhibition. Finally, m-CT imaging in live KrasG12D-LSL mice showed reduction of tumor burdens in PD-0325901-treated animals at sub-MTD dose. In conclusion, our data suggest that PD-0325901 at doses below MTD is still a potent compound capable of tumor growth inhibition where Kras and/or PI3K are drivers of tumor growth and progression.

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Authors and Affiliations

  1. Oncology Research Unit, Pfizer Global R&D, 10724 Science Center Dr., La Jolla, San Diego, CA, 92121, USA

    Brett H. Simmons, Joseph H. Lee, Julie L. Kan, James G. Christensen & Farbod Shojaei

  2. Department of Comparative Medicine, Pfizer Global R&D, 10724 Science Center Dr., La Jolla, San Diego, CA, 92121, USA

    Kush Lalwani, Anand Giddabasappa & Jeetendra Eswaraka

  3. Department of Drug Safety Research & Development, Pfizer Global R&D, 10724 Science Center Dr., La Jolla, San Diego, CA, 92121, USA

    Brittany A. Snider, Anthony Wong & Patrick B. Lappin

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  1. Brett H. Simmons
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  2. Joseph H. Lee
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  3. Kush Lalwani
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Correspondence to Farbod Shojaei.

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Brett H. Simmons and Joseph H. Lee equally contributed to this work.

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Simmons, B.H., Lee, J.H., Lalwani, K. et al. Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in KrasG12D-LSL mice. Cancer Chemother Pharmacol 70, 213–220 (2012). https://doi.org/10.1007/s00280-012-1899-6

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  • DOI: https://doi.org/10.1007/s00280-012-1899-6

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