PIK3CA hotspot mutations differentially impact responses to MET targeting in MET-driven and non-driven preclinical cancer models.

Nisa Hernández, Lluís; Häfliger, Pascal; Poliakova, Michaela; Giger, Roland; Francica, Paola; Aebersold, Daniel; Charles, Roch-Philippe; Zimmer, Yitzhak; Medova, Michaela (2017). PIK3CA hotspot mutations differentially impact responses to MET targeting in MET-driven and non-driven preclinical cancer models. Molecular cancer, 16(1), p. 93. BioMed Central 10.1186/s12943-017-0660-5

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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(E545K) and PIK3CA(H1047R), 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(E545K) and PIK3CA(H1047R) confer resistance to MET inhibition in MET-driven models. PIK3CA(H1047R) was more potent than PIK3CA(E545K) 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(H1047R). 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ear, Nose and Throat Disorders (ENT)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Nisa Hernández, Lluís; Häfliger, Pascal; Poliakova, Michaela; Giger, Roland; Francica, Paola; Aebersold, Daniel; Charles, Roch-Philippe; Zimmer, Yitzhak and Medova, Michaela

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1476-4598

Publisher:

BioMed Central

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

09 Feb 2018 10:17

Last Modified:

11 Feb 2018 02:22

Publisher DOI:

10.1186/s12943-017-0660-5

PubMed ID:

28532501

Uncontrolled Keywords:

Head and neck cancer MET receptor tyrosine kinase PI3K pathway PIK3CA mutations Resistance mechanisms

BORIS DOI:

10.7892/boris.105274

URI:

https://boris.unibe.ch/id/eprint/105274

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