Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer

Piergiorgio Pettazzoni, Andrea Viale, Parantu Shah, Alessandro Carugo, Haoqiang Ying, Huamin Wang, Giannicola Genovese, Sahil Seth, Rosalba Minelli, Tessa Green, Emmet Huang-Hobbs, Denise Corti, Nora Sanchez, Luigi Nezi, Matteo Marchesini, Avnish Kapoor, Wantong Yao, Maria E. Di Francesco, Alessia Petrocchi, Angela K. Deem & 9 others Kenneth Scott, Simona Colla, Gordon Mills, Jason B. Fleming, Timothy P. Heffernan, Philip Jones, Carlo Toniatti, Ronald A. Depinho, Giulio F. Draetta

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Mutated KRAS (KRAS∗) is a fundamental driver in the majority of pancreatic ductal adenocarcinomas (PDAC). Using an inducible mouse model of KRAS∗-driven PDAC, we compared KRAS∗ genetic extinction with pharmacologic inhibition of MEK1 in tumor spheres and in vivo. KRAS∗ ablation blocked proliferation and induced apoptosis, whereas MEK1 inhibition exerted cytostatic effects. Proteomic analysis evidenced that MEK1 inhibition was accompanied by a sustained activation of the PI3K-AKT-MTOR pathway and by the activation of AXL, PDGFRa, and HER1-2 receptor tyrosine kinases (RTK) expressed in a large proportion of human PDAC samples analyzed. Although single inhibition of each RTK alone or plus MEK1 inhibitors was ineffective, a combination of inhibitors targeting all three coactivated RTKs and MEK1 was needed to inhibit proliferation and induce apoptosis in both mouse and human low-passage PDAC cultures. Importantly, constitutive AKT activation, which may mimic the fraction of AKT2-amplified PDAC, was able to bypass the induction of apoptosis caused by KRAS∗ ablation, highlighting a potential inherent resistance mechanism that may inform the clinical application of MEK inhibitor therapy. This study suggests that combinatorial-targeted therapies for pancreatic cancer must be informed by the activation state of each putative driver in a given treatment context. In addition, our work may offer explanative and predictive power in understanding why inhibitors of EGFR signaling fail in PDAC treatment and how drug resistance mechanisms may arise in strategies to directly target KRAS.

Original languageEnglish (US)
Pages (from-to)1091-1101
Number of pages11
JournalCancer Research
Volume75
Issue number6
DOIs
StatePublished - Mar 15 2015
Externally publishedYes

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Mitogen-Activated Protein Kinase Kinases
Receptor Protein-Tyrosine Kinases
Pancreatic Neoplasms
Adenocarcinoma
Apoptosis
Therapeutics
TYK2 Kinase
Cytostatic Agents
Phosphatidylinositol 3-Kinases
Drug Resistance
Proteomics
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. / Pettazzoni, Piergiorgio; Viale, Andrea; Shah, Parantu; Carugo, Alessandro; Ying, Haoqiang; Wang, Huamin; Genovese, Giannicola; Seth, Sahil; Minelli, Rosalba; Green, Tessa; Huang-Hobbs, Emmet; Corti, Denise; Sanchez, Nora; Nezi, Luigi; Marchesini, Matteo; Kapoor, Avnish; Yao, Wantong; Di Francesco, Maria E.; Petrocchi, Alessia; Deem, Angela K.; Scott, Kenneth; Colla, Simona; Mills, Gordon; Fleming, Jason B.; Heffernan, Timothy P.; Jones, Philip; Toniatti, Carlo; Depinho, Ronald A.; Draetta, Giulio F.

In: Cancer Research, Vol. 75, No. 6, 15.03.2015, p. 1091-1101.

Research output: Contribution to journalArticle

Pettazzoni, P, Viale, A, Shah, P, Carugo, A, Ying, H, Wang, H, Genovese, G, Seth, S, Minelli, R, Green, T, Huang-Hobbs, E, Corti, D, Sanchez, N, Nezi, L, Marchesini, M, Kapoor, A, Yao, W, Di Francesco, ME, Petrocchi, A, Deem, AK, Scott, K, Colla, S, Mills, G, Fleming, JB, Heffernan, TP, Jones, P, Toniatti, C, Depinho, RA & Draetta, GF 2015, 'Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer', Cancer Research, vol. 75, no. 6, pp. 1091-1101. https://doi.org/10.1158/0008-5472.CAN-14-1854
Pettazzoni, Piergiorgio ; Viale, Andrea ; Shah, Parantu ; Carugo, Alessandro ; Ying, Haoqiang ; Wang, Huamin ; Genovese, Giannicola ; Seth, Sahil ; Minelli, Rosalba ; Green, Tessa ; Huang-Hobbs, Emmet ; Corti, Denise ; Sanchez, Nora ; Nezi, Luigi ; Marchesini, Matteo ; Kapoor, Avnish ; Yao, Wantong ; Di Francesco, Maria E. ; Petrocchi, Alessia ; Deem, Angela K. ; Scott, Kenneth ; Colla, Simona ; Mills, Gordon ; Fleming, Jason B. ; Heffernan, Timothy P. ; Jones, Philip ; Toniatti, Carlo ; Depinho, Ronald A. ; Draetta, Giulio F. / Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. In: Cancer Research. 2015 ; Vol. 75, No. 6. pp. 1091-1101.
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abstract = "Mutated KRAS (KRAS∗) is a fundamental driver in the majority of pancreatic ductal adenocarcinomas (PDAC). Using an inducible mouse model of KRAS∗-driven PDAC, we compared KRAS∗ genetic extinction with pharmacologic inhibition of MEK1 in tumor spheres and in vivo. KRAS∗ ablation blocked proliferation and induced apoptosis, whereas MEK1 inhibition exerted cytostatic effects. Proteomic analysis evidenced that MEK1 inhibition was accompanied by a sustained activation of the PI3K-AKT-MTOR pathway and by the activation of AXL, PDGFRa, and HER1-2 receptor tyrosine kinases (RTK) expressed in a large proportion of human PDAC samples analyzed. Although single inhibition of each RTK alone or plus MEK1 inhibitors was ineffective, a combination of inhibitors targeting all three coactivated RTKs and MEK1 was needed to inhibit proliferation and induce apoptosis in both mouse and human low-passage PDAC cultures. Importantly, constitutive AKT activation, which may mimic the fraction of AKT2-amplified PDAC, was able to bypass the induction of apoptosis caused by KRAS∗ ablation, highlighting a potential inherent resistance mechanism that may inform the clinical application of MEK inhibitor therapy. This study suggests that combinatorial-targeted therapies for pancreatic cancer must be informed by the activation state of each putative driver in a given treatment context. In addition, our work may offer explanative and predictive power in understanding why inhibitors of EGFR signaling fail in PDAC treatment and how drug resistance mechanisms may arise in strategies to directly target KRAS.",
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AU - Pettazzoni, Piergiorgio

AU - Viale, Andrea

AU - Shah, Parantu

AU - Carugo, Alessandro

AU - Ying, Haoqiang

AU - Wang, Huamin

AU - Genovese, Giannicola

AU - Seth, Sahil

AU - Minelli, Rosalba

AU - Green, Tessa

AU - Huang-Hobbs, Emmet

AU - Corti, Denise

AU - Sanchez, Nora

AU - Nezi, Luigi

AU - Marchesini, Matteo

AU - Kapoor, Avnish

AU - Yao, Wantong

AU - Di Francesco, Maria E.

AU - Petrocchi, Alessia

AU - Deem, Angela K.

AU - Scott, Kenneth

AU - Colla, Simona

AU - Mills, Gordon

AU - Fleming, Jason B.

AU - Heffernan, Timothy P.

AU - Jones, Philip

AU - Toniatti, Carlo

AU - Depinho, Ronald A.

AU - Draetta, Giulio F.

PY - 2015/3/15

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N2 - Mutated KRAS (KRAS∗) is a fundamental driver in the majority of pancreatic ductal adenocarcinomas (PDAC). Using an inducible mouse model of KRAS∗-driven PDAC, we compared KRAS∗ genetic extinction with pharmacologic inhibition of MEK1 in tumor spheres and in vivo. KRAS∗ ablation blocked proliferation and induced apoptosis, whereas MEK1 inhibition exerted cytostatic effects. Proteomic analysis evidenced that MEK1 inhibition was accompanied by a sustained activation of the PI3K-AKT-MTOR pathway and by the activation of AXL, PDGFRa, and HER1-2 receptor tyrosine kinases (RTK) expressed in a large proportion of human PDAC samples analyzed. Although single inhibition of each RTK alone or plus MEK1 inhibitors was ineffective, a combination of inhibitors targeting all three coactivated RTKs and MEK1 was needed to inhibit proliferation and induce apoptosis in both mouse and human low-passage PDAC cultures. Importantly, constitutive AKT activation, which may mimic the fraction of AKT2-amplified PDAC, was able to bypass the induction of apoptosis caused by KRAS∗ ablation, highlighting a potential inherent resistance mechanism that may inform the clinical application of MEK inhibitor therapy. This study suggests that combinatorial-targeted therapies for pancreatic cancer must be informed by the activation state of each putative driver in a given treatment context. In addition, our work may offer explanative and predictive power in understanding why inhibitors of EGFR signaling fail in PDAC treatment and how drug resistance mechanisms may arise in strategies to directly target KRAS.

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