Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models

Hua Zhong, Cesar Sanchez, Dirk Spitrzer, Stacy Plambeck-Suess, Jesse Gibbs, Williams G. Hawkins, David Denardo, Feng Gao, Robert A. Pufahl, Albert Lockhart, Mai Xu, David Linehan, Jason Weber, Andrea Wang-Gillam

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK [MEK]). We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type) and MIA PaCa-2 (KRAS mutated) cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1) and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.

Original languageEnglish (US)
Article numbere77243
JournalPLoS One
Volume8
Issue number10
DOIs
StatePublished - Oct 9 2013
Externally publishedYes

Fingerprint

MAP Kinase Kinase Kinase 3
pancreatic neoplasms
1-Phosphatidylinositol 4-Kinase
Mitogen-Activated Protein Kinase Kinases
phosphatidylinositol 3-kinase
Phosphatidylinositols
Pancreatic Neoplasms
Cells
S 6
Phosphorylation
cell lines
Heterografts
Cell Line
cell viability
Cell Survival
phosphorylation
apoptosis
MAP Kinase Kinase 3
Apoptosis
Cell signaling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Zhong, H., Sanchez, C., Spitrzer, D., Plambeck-Suess, S., Gibbs, J., Hawkins, W. G., ... Wang-Gillam, A. (2013). Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models. PLoS One, 8(10), [e77243]. https://doi.org/10.1371/journal.pone.0077243

Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models. / Zhong, Hua; Sanchez, Cesar; Spitrzer, Dirk; Plambeck-Suess, Stacy; Gibbs, Jesse; Hawkins, Williams G.; Denardo, David; Gao, Feng; Pufahl, Robert A.; Lockhart, Albert; Xu, Mai; Linehan, David; Weber, Jason; Wang-Gillam, Andrea.

In: PLoS One, Vol. 8, No. 10, e77243, 09.10.2013.

Research output: Contribution to journalArticle

Zhong, H, Sanchez, C, Spitrzer, D, Plambeck-Suess, S, Gibbs, J, Hawkins, WG, Denardo, D, Gao, F, Pufahl, RA, Lockhart, A, Xu, M, Linehan, D, Weber, J & Wang-Gillam, A 2013, 'Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models', PLoS One, vol. 8, no. 10, e77243. https://doi.org/10.1371/journal.pone.0077243
Zhong H, Sanchez C, Spitrzer D, Plambeck-Suess S, Gibbs J, Hawkins WG et al. Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models. PLoS One. 2013 Oct 9;8(10). e77243. https://doi.org/10.1371/journal.pone.0077243
Zhong, Hua ; Sanchez, Cesar ; Spitrzer, Dirk ; Plambeck-Suess, Stacy ; Gibbs, Jesse ; Hawkins, Williams G. ; Denardo, David ; Gao, Feng ; Pufahl, Robert A. ; Lockhart, Albert ; Xu, Mai ; Linehan, David ; Weber, Jason ; Wang-Gillam, Andrea. / Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models. In: PLoS One. 2013 ; Vol. 8, No. 10.
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abstract = "Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK [MEK]). We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type) and MIA PaCa-2 (KRAS mutated) cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1) and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.",
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