PIK3CA Hotspot Mutations Differentially Impact Responses to MET Targeting in MET-driven and Non-driven Preclinical Cancer Models

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2017 May 24

PMID 28532501

Citations 12

Authors

Lluis Nisa

Pascal Hafliger

Michaela Poliakova

Roland Giger

Paola Francica

Daniel Matthias Aebersold

Roch-Philippe Charles

Yitzhak Zimmer

Michaela Medova

Affiliations

Soon will be listed here.

Abstract

Background: The MET receptor tyrosine kinase represents a promising target in cancer. PIK3CA activating mutations are common in several tumor types and can potentially confer resistance to anti-receptor tyrosine kinase therapy.

Methods: MET and/or PI3K pathway inhibition was assessed in NIH3T3 cells harboring MET-activating point mutation with or without ectopic expression of PIK3CA and PIK3CA, as well as in MET-expressing head and neck cancer cells with endogenous PIK3CA mutations. Endpoints included PI3K pathway activation, cell proliferation, colony-forming ability, cell death, wound-healing, and an in vivo model.

Results: PIK3CA and PIK3CA confer resistance to MET inhibition in MET-driven models. PIK3CA was more potent than PIK3CA at inducing resistance in PI3K pathway activation, cell proliferation, colony-forming ability, induction of cell death and wound-healing upon MET inhibition. Resistance to MET inhibition could be synergistically overcome by co-targeting PI3K. Furthermore, combined MET/PI3K inhibition led to enhanced anti-tumor activity in vivo in tumors harboring PIK3CA. In head and neck cancer cells the combination of MET/PI3K inhibitors led to more-than-additive effects.

Conclusions: PIK3CA mutations can lead to resistance to MET inhibition, supporting future clinical evaluation of combinations of PI3K and MET inhibitors in common scenarios of malignant neoplasms featuring aberrant MET expression and PIK3CA mutations.

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References

Zimmer Y, Vaseva A, Medova M, Streit B, Blank-Liss W, Greiner R . Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274. Cancer Lett. 2009; 289(2):228-36. DOI: 10.1016/j.canlet.2009.08.017. View

Nanda R . Targeting the human epidermal growth factor receptor 2 (HER2) in the treatment of breast cancer: recent advances and future directions. Rev Recent Clin Trials. 2008; 2(2):111-6. DOI: 10.2174/157488707780599375. View

Di Fiore F, Sesboue R, Michel P, Sabourin J, Frebourg T . Molecular determinants of anti-EGFR sensitivity and resistance in metastatic colorectal cancer. Br J Cancer. 2010; 103(12):1765-72. PMC: 3008616. DOI: 10.1038/sj.bjc.6606008. View

Fiordalisi J, Johnson 2nd R, Ulku A, Der C, Cox A . Mammalian expression vectors for Ras family proteins: generation and use of expression constructs to analyze Ras family function. Methods Enzymol. 2001; 332:3-36. DOI: 10.1016/s0076-6879(01)32189-4. View

Kanteti R, Dhanasingh I, Kawada I, Lennon F, Arif Q, Bueno R . MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma. PLoS One. 2014; 9(9):e105919. PMC: 4164360. DOI: 10.1371/journal.pone.0105919. View

Ray M, Salgia R, Vokes E . The role of EGFR inhibition in the treatment of non-small cell lung cancer. Oncologist. 2009; 14(11):1116-30. DOI: 10.1634/theoncologist.2009-0054. View

Fruman D, Rommel C . PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014; 13(2):140-56. PMC: 3994981. DOI: 10.1038/nrd4204. View

Lui V, Hedberg M, Li H, Vangara B, Pendleton K, Zeng Y . Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013; 3(7):761-9. PMC: 3710532. DOI: 10.1158/2159-8290.CD-13-0103. View

Vaira V, Fedele G, Pyne S, Fasoli E, Zadra G, Bailey D . Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors. Proc Natl Acad Sci U S A. 2010; 107(18):8352-6. PMC: 2889536. DOI: 10.1073/pnas.0907676107. View

10.

Chen L, Cohen E, Grandis J . New strategies in head and neck cancer: understanding resistance to epidermal growth factor receptor inhibitors. Clin Cancer Res. 2010; 16(9):2489-95. PMC: 2887084. DOI: 10.1158/1078-0432.CCR-09-2318. View

11.

Weinstein I, Joe A . Mechanisms of disease: Oncogene addiction--a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. 2006; 3(8):448-57. DOI: 10.1038/ncponc0558. View

12.

Avan A, Maftouh M, Funel N, Ghayour-Mobarhan M, Boggi U, Peters G . MET as a potential target for the treatment of upper gastrointestinal cancers: characterization of novel c-Met inhibitors from bench to bedside. Curr Med Chem. 2013; 21(8):975-89. DOI: 10.2174/09298673113209990231. View

13.

Singleton K, Kim J, Hinz T, Marek L, Casas-Selves M, Hatheway C . A receptor tyrosine kinase network composed of fibroblast growth factor receptors, epidermal growth factor receptor, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, and hepatocyte growth factor receptor drives growth and survival of head.... Mol Pharmacol. 2013; 83(4):882-93. PMC: 3608435. DOI: 10.1124/mol.112.084111. View

14.

Medova M, Pochon B, Streit B, Blank-Liss W, Francica P, Stroka D . The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants. Mol Cancer Ther. 2013; 12(11):2415-24. DOI: 10.1158/1535-7163.MCT-13-0151. View

15.

Gelsomino F, Facchinetti F, Haspinger E, Garassino M, Trusolino L, de Braud F . Targeting the MET gene for the treatment of non-small-cell lung cancer. Crit Rev Oncol Hematol. 2013; 89(2):284-99. DOI: 10.1016/j.critrevonc.2013.11.006. View

16.

Engelman J, Luo J, Cantley L . The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006; 7(8):606-19. DOI: 10.1038/nrg1879. View

17.

Seiwert T, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El Dinali M . The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer Res. 2009; 69(7):3021-31. PMC: 2871252. DOI: 10.1158/0008-5472.CAN-08-2881. View

18.

Trejo C, Green S, Marsh V, Collisson E, Iezza G, Phillips W . Mutationally activated PIK3CA(H1047R) cooperates with BRAF(V600E) to promote lung cancer progression. Cancer Res. 2013; 73(21):6448-61. PMC: 3825323. DOI: 10.1158/0008-5472.CAN-13-0681. View

19.

Wang Z, Martin D, Molinolo A, Patel V, Iglesias-Bartolome R, Degese M . mTOR co-targeting in cetuximab resistance in head and neck cancers harboring PIK3CA and RAS mutations. J Natl Cancer Inst. 2014; 106(9). PMC: 4133928. DOI: 10.1093/jnci/dju215. View

20.

Young N, Liu J, Pierce C, Wei T, Grushko T, Olopade O . Molecular phenotype predicts sensitivity of squamous cell carcinoma of the head and neck to epidermal growth factor receptor inhibition. Mol Oncol. 2012; 7(3):359-68. PMC: 3661759. DOI: 10.1016/j.molonc.2012.11.001. View