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16P - Inhibition of PDE4 sensitizes drug resistant NSCLC to TKI therapy (ID 189)

Presentation Number
16P
Lecture Time
18:25 - 18:25
Speakers
  • S. Mukherjee
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • S. Mukherjee
  • D. Suresh
  • A. Upendran
  • R. Kannan

Abstract

Background

NSCLC patients undergoing tyrosine kinase inhibitor (TKI) therapy often develop resistance (9-12 months) resulting in low median survival (10-14 months) among stage IV patients. Studies showed that, in some cases, the resistance can be attributed to upregulation of pro-survival PI3K-Akt pathway. Indeed, EGFR-mutant patients with elevated levels of phospho-Akt have shown poor therapeutic response and the levels of p-Akt are increased upon prolonged EGFR TK treatment. In addition, several mechanistic studies attribute increased phospho-Akt (p-Akt) levels in tumor as one of the reasons for drug resistance. In an independent study, researchers have shown that suppression of phosphorylation of Akt can be achieved by inhibition of Phosphodiesterase- 4(PDE4) and in turn activate luminal apoptosis. Therefore, we hypothesized that PDE4 inhibition would sensitize drug resistant NSCLC to tyrosine kinase inhibitor therapy by abrogating the PI3K-Akt pathway.

Methods

TK resistant cell lines along with controls were used for the study. First generation TKIs, Dasatinib, Erlotinib and Gefitinib were used to study the efficacy of TKI. Roflumilast, a drug already used in chronic obstructive pulmonary disorder (COPD), was used as the PDE4 inhibitor.

Results

Inhibition of PDE4 followed by treatment with TKIs showed remarkable decrease in IC50values, compared to either PDE4 inhibition or TK inhibition. Upon PDE4 inhibition, efficacy of TKIs is found to be increased several folds compared to individual inhibitors. Cells showed no signs toxicity to the PDE4 inhibitor at the dose levels used, thus making the inhibitor itself absolutely nontoxic at this treatment dose.

Conclusions

Our results suggest that PDE4 inhibition is a potential way to reverse TKI resistance and also to improve TKI therapy in patients with high levels of p-Akt.

Legal entity responsible for the study

University of Missouri - Columbia, Missouri, USA.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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