Effects of AKT Inhibition on HGF-mediated Erlotinib Resistance in Non-small Cell Lung Cancer Cell Lines

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2014 Oct 18

PMID 25323938

Citations 13

Authors

William S Holland

Danielle C Chinn

Primo N Lara Jr

David R Gandara

Philip C Mack

Affiliations

Soon will be listed here.

Abstract

Purpose: Acquired resistance to erlotinib in patients with EGFR-mutant non-small cell lung cancer can result from aberrant activation of alternative receptor tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine whether inhibition of AKT signaling could augment erlotinib activity and abrogate HGF-mediated resistance.

Methods: The effects of MK-2206, a selective AKT inhibitor, were evaluated in combination with erlotinib on a large panel of 13 lung cancer cell lines containing different EGFR or KRAS abnormalities. The activity of the combination was assessed using proliferation assays, flow cytometry and immunoblotting. The MEK inhibitor PD0325901 was used to determine the role of the MAP kinase pathway in erlotinib resistance.

Results: The combination of MK-2206 and erlotinib resulted in synergistic growth inhibition independent of EGFR mutation status. In cell lines where HGF blocked the anti-proliferative and cytotoxic effects of erlotinib, MK-2206 could restore cell cycle arrest, but MEK inhibition was required for erlotinib-dependent apoptosis. Both AKT and MEK inhibition contributed to cell death independent of erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested.

Conclusions: These findings illustrate the potential advantages and challenges of combined signal transduction inhibition as a generalized strategy to circumvent acquired erlotinib resistance.

Citing Articles

An original aneuploidy-related gene model for predicting lung adenocarcinoma survival and guiding therapy.

Zhang Y, Li D Sci Rep. 2024; 14(1):8135.

PMID: 38584220 PMC: 10999435. DOI: 10.1038/s41598-024-58020-y.

Involvement of the AKT Pathway in Resistance to Erlotinib and Cabozantinib in Triple-Negative Breast Cancer Cell Lines.

Lefebvre C, Pellizzari S, Bhat V, Jurcic K, Litchfield D, Allan A Biomedicines. 2023; 11(9).

PMID: 37760847 PMC: 10525382. DOI: 10.3390/biomedicines11092406.

A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non-Small Cell Lung Cancer.

Woo X, Srivastava A, Mack P, Graber J, Sanderson B, Lloyd M Cancer Res. 2022; 82(22):4126-4138.

PMID: 36069866 PMC: 9664138. DOI: 10.1158/0008-5472.CAN-22-0948.

The Root Extract of Dunn Exerts Anticancer Effects in Human Non-Small-Cell Lung Cancer Cells with Different Mutation Statuses by Suppressing MET Activity.

Park H, Jeong J, Park S Molecules. 2022; 27(7).

PMID: 35408753 PMC: 9000538. DOI: 10.3390/molecules27072360.

Overexpression of miR-31-5p inhibits human chordoma cells proliferation and invasion by targeting the oncogene c-Met through suppression of AKT/PI3K signaling pathway.

Wang W, Tang L, Li Q, Tan J, Yao H, Duan Z Int J Clin Exp Pathol. 2020; 10(7):8000-8009.

PMID: 31966652 PMC: 6965250.

References

Weinstein I . Cancer. Addiction to oncogenes--the Achilles heal of cancer. Science. 2002; 297(5578):63-4. DOI: 10.1126/science.1073096. View

Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K . MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010; 9(7):1956-67. DOI: 10.1158/1535-7163.MCT-09-1012. View

Vasudevan K, Barbie D, Davies M, Rabinovsky R, McNear C, Kim J . AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009; 16(1):21-32. PMC: 2752826. DOI: 10.1016/j.ccr.2009.04.012. View

Rashmi R, DeSelm C, Helms C, Bowcock A, Rogers B, Rader J . AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake. PLoS One. 2014; 9(4):e92948. PMC: 3976291. DOI: 10.1371/journal.pone.0092948. View

Iida M, Brand T, Campbell D, Starr M, Luthar N, Traynor A . Targeting AKT with the allosteric AKT inhibitor MK-2206 in non-small cell lung cancer cells with acquired resistance to cetuximab. Cancer Biol Ther. 2013; 14(6):481-91. PMC: 3813564. DOI: 10.4161/cbt.24342. View

Yamada T, Matsumoto K, Wang W, Li Q, Nishioka Y, Sekido Y . Hepatocyte growth factor reduces susceptibility to an irreversible epidermal growth factor receptor inhibitor in EGFR-T790M mutant lung cancer. Clin Cancer Res. 2009; 16(1):174-83. DOI: 10.1158/1078-0432.CCR-09-1204. View

Hirsch F, Varella-Garcia M, Bunn Jr P, Franklin W, Dziadziuszko R, Thatcher N . Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol. 2006; 24(31):5034-42. DOI: 10.1200/JCO.2006.06.3958. View

Engelman J, Janne P . Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res. 2008; 14(10):2895-9. DOI: 10.1158/1078-0432.CCR-07-2248. View

Barnett S, Defeo-Jones D, Fu S, Hancock P, Haskell K, Jones R . Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. Biochem J. 2004; 385(Pt 2):399-408. PMC: 1134710. DOI: 10.1042/BJ20041140. View

10.

Gadgeel S, Wozniak A . Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer. Clin Lung Cancer. 2013; 14(4):322-32. DOI: 10.1016/j.cllc.2012.12.001. View

11.

Yap T, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K . First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol. 2011; 29(35):4688-95. DOI: 10.1200/JCO.2011.35.5263. View

12.

Menakongka A, Suthiphongchai T . Involvement of PI3K and ERK1/2 pathways in hepatocyte growth factor-induced cholangiocarcinoma cell invasion. World J Gastroenterol. 2010; 16(6):713-22. PMC: 2817059. DOI: 10.3748/wjg.v16.i6.713. View

13.

Niederst M, Engelman J . Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal. 2013; 6(294):re6. PMC: 3876281. DOI: 10.1126/scisignal.2004652. View

14.

Konopleva M, Walter R, Faderl S, Jabbour E, Zeng Z, Borthakur G . Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia. Clin Cancer Res. 2014; 20(8):2226-35. PMC: 3989412. DOI: 10.1158/1078-0432.CCR-13-1978. View

15.

Shepherd F, Pereira J, Ciuleanu T, Tan E, Hirsh V, Thongprasert S . Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005; 353(2):123-32. DOI: 10.1056/NEJMoa050753. View

16.

Sano T, Takeuchi S, Nakagawa T, Ishikawa D, Nanjo S, Yamada T . The novel phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor, BEZ235, circumvents erlotinib resistance of epidermal growth factor receptor mutant lung cancer cells triggered by hepatocyte growth factor. Int J Cancer. 2013; 133(2):505-13. DOI: 10.1002/ijc.28034. View

17.

Cheng Y, Zhang Y, Zhang L, Ren X, Huber-Keener K, Liu X . MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis. Mol Cancer Ther. 2011; 11(1):154-64. PMC: 3302182. DOI: 10.1158/1535-7163.MCT-11-0606. View

18.

Sos M, Fischer S, Ullrich R, Peifer M, Heuckmann J, Koker M . Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci U S A. 2009; 106(43):18351-6. PMC: 2757399. DOI: 10.1073/pnas.0907325106. View

19.

Yano S, Yamada T, Takeuchi S, Tachibana K, Minami Y, Yatabe Y . Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort. J Thorac Oncol. 2011; 6(12):2011-7. DOI: 10.1097/JTO.0b013e31823ab0dd. View

20.

Ma P, Tretiakova M, Nallasura V, Jagadeeswaran R, Husain A, Salgia R . Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion. Br J Cancer. 2007; 97(3):368-77. PMC: 2360323. DOI: 10.1038/sj.bjc.6603884. View