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Phosphodiesterase Inhibition to Sensitize Non-Small-Cell Lung Cancer to Pemetrexed: A Double-Edged Strategy
Anna V Ivanina Foureau1, David M Foureau2, Cody C McHale3
1Translational Research, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA.
Abstract:
Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical inhibitors of PDE5, 8, 9, or 10, against squamous and non-squamous NCSLC cells. Genomic alterations to PDE genes (PDEmut) or PDE biochemical inhibition (PDEi) can sensitize NSCLC to PMX in vitro (observed in 50% NSCLC evaluated). The synergistic activity of PDEi with PMX required microdosing of the anti-folate drug. As single agents, none of the PDEis evaluated have anti-tumor activity. PDE biochemical inhibitors, targeting either cAMP or cGMP signaling (or both), resulted in significant cross-modulation of downstream pathways. The use of PDEi may present a new strategy to overcome PMX resistance of PDEwt NSCLC tumors but comes with important caveats, including the use of subtherapeutic PMX doses.
Insights
Combining phosphodiesterase inhibitors (PDEi) with pemetrexed (PMX) shows anti-tumor activity in non-small-cell lung cancer (NSCLC). This strategy requires microdosing PMX and may overcome resistance in certain NSCLC tumors.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Phosphodiesterases (PDEs) regulate cyclic nucleotide signaling and are implicated in cancer hallmarks and chemotherapy resistance in non-small-cell lung cancer (NSCLC).
- Pemetrexed (PMX) is an anti-folate chemotherapy agent used in NSCLC treatment.
Purpose of the Study:
- To evaluate the anti-tumor activity of PMX, alone or combined with PDE inhibitors (PDEi) targeting PDE5, 8, 9, or 10, against NSCLC cells.
- To determine if PDE inhibition can sensitize NSCLC to PMX and overcome resistance.
Main Methods:
- In vitro evaluation of PMX combined with PDE biochemical inhibitors (PDEi) against squamous and non-squamous NSCLC cell lines.
- Assessment of synergistic activity requiring microdosing of PMX.
- Analysis of downstream pathway modulation by PDEi targeting cAMP or cGMP signaling.
Main Results:
- Genomic alterations in PDE genes (PDEmut) or PDE inhibition (PDEi) sensitized 50% of evaluated NSCLC cells to PMX in vitro.
- Synergistic effects of PDEi and PMX were observed specifically with microdosing of PMX.
- Single-agent PDEi showed no anti-tumor activity, but PDEi modulated downstream signaling pathways.
Conclusions:
- PDE inhibitors may offer a novel strategy to overcome pemetrexed resistance in wild-type PDE (PDEwt) NSCLC tumors.
- This approach necessitates the use of sub-therapeutic doses of PMX and careful consideration of caveats.
- The combination strategy highlights the complex interplay between PDE signaling and chemotherapy response in NSCLC.
