Alternative dosing of dual PI3K and MEK inhibition in cancer therapyReport as inadecuate




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BMC Cancer

, 12:612

Experimental therapeutics and drug development

Abstract

BackgroundPI3K-AKT-mTOR and RAS-RAF-MEK-ERK pathways are thought to be the central transducers of oncogenic signals in solid malignancies, and there has been a lot of enthusiasm for developing inhibitors of these pathways for cancer therapy. Some preclinical models have suggested that combining inhibitors of both parallel pathways may be more efficacious, but it remains unknown whether dual inhibition with high enough concentrations of the drugs to achieve meaningful target inhibition is tolerable in a clinical setting. Furthermore, the predictive factors for dual inhibition are unknown.

MethodsNon-small cell lung cancer NSCLC cell lines n=12 with the most frequent oncogenic backgrounds K-Ras mut n=3, EGFR mut n=3, ALK translocated n=3, and triple-negative n=3 were exposed to PI3K inhibitors ZSTK474, PI-103 or MEK inhibitor CI-1040 alone or in combination and analysed with an MTS growth-cytotoxicity assay and statistically by combination index analysis. The activity of the intracellular signaling pathways in response to the inhibitor treatments was analysed with a western blot using phospho-specific antibodies to AKT, ERK1-2, S6, and 4E-BPI. For the differential dosing schedule experiments, additional breast and colon cancer cell lines known to be sensitive to dual inhibition were included.

ResultsTwo of the 12 NSCLC cell lines tested, H3122 ALK translocated and H1437 triple-negative, showed increased cytotoxicity upon dual MEK and PI3K inhibition. Furthermore, MDA-MB231 breast and HCT116 colon, showed increased cytotoxicity upon dual inhibition, as in previous studies. Activation of parallel pathways in the dual inhibition-sensitive lines was also noted in response to single inhibitor treatment. Otherwise, no significant differences in downstream intracellular pathway activity S6 and 4E-BPI were noted between PI3K alone and dual inhibition other than the increased cytotoxicity of the latter. In the alternative dosing schedules two out of the four dual inhibition-sensitive cell lines showed similar cytotoxicity to continuous PI3K and short 15min MEK inhibition treatment.

ConclusionsTherapy with a dual PI3K and MEK inhibitor combination is more efficient than either inhibitor alone in some NSCLC cell lines. Responses to dual inhibition were not associated with any specific oncogenic genotype and no other predictive factors for dual inhibition were noted. The maximal effect of the dual PI3K and MEK inhibition can be achieved with alternative dosing schedules which are potentially more tolerable clinically.

KeywordsNon-small cell lung cancer PI3K inhibition MEK inhibition Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-12-612 contains supplementary material, which is available to authorized users.

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Author: Elina Jokinen - Niina Laurila - Jussi P Koivunen

Source: https://link.springer.com/



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