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Published on: December 21, 2019
Targeting MYC sensitizes malignant mesothelioma cells to PAK blockage-induced cytotoxicity
Yinfei Tan1, Eleonora Sementino1, Jonathan Chernoff1
1Cancer Biology Program, Fox Chase Cancer CenterPhiladelphia, Pennsylvania, USA.
Abstract:
Clinical management of malignant mesothelioma (MM) is very challenging due to marked resistance of this tumor to chemotherapy. Various mechanisms lead to a less than ideal drug concentration inside of MM cells, diminishing cytotoxicity. Consequently, single cytotoxic drugs achieve very modest response rates in MM patients, and combination regimens using standard and novel therapies have achieved only limited improvement in overall survival. Here, we demonstrate that MYC has either proliferative or pro-survival effects in MM cells during normal or stressed conditions, respectively. A MYC inhibitor 10058-F4 reduced MM cell proliferation via down regulation of cyclin D. Under serum starvation conditions, MM cells became quiescent, and the addition of MYC inhibitors triggered apoptosis in the resting MM cells. We also found that high concentrations of the PAK inhibitor PF3758309 killed MM cells, but the drug had only cytostatic effects at lower concentrations. These quiescent cells underwent apoptosis upon pharmacological inhibition of MYC. A novel MYC inhibitor KJ-Pyr-9 and a newer PAK inhibitor, FRAX597, also demonstrated marked cytotoxic cooperativity. Collectively, these findings demonstrate that targeting of MYC can sensitize MM cells and provide rationale for inhibition of MYC and PAK as a novel combinatory regimen for the treatment of this otherwise therapy-resistant, clinically incurable malignancy.
Insights
Targeting MYC can overcome chemotherapy resistance in malignant mesothelioma (MM). Inhibiting MYC and PAK together shows promise for treating this incurable cancer.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Malignant mesothelioma (MM) exhibits significant resistance to chemotherapy, limiting treatment efficacy.
- Poor drug penetration into MM cells reduces cytotoxicity, resulting in modest response rates.
- Current combination therapies offer limited improvements in overall survival for MM patients.
Purpose of the Study:
- To investigate the role of MYC in MM cell proliferation and survival.
- To evaluate the efficacy of MYC inhibitors alone and in combination with PAK inhibitors.
- To explore novel therapeutic strategies for chemo-resistant malignant mesothelioma.
Main Methods:
- Utilized MYC inhibitors (10058-F4, KJ-Pyr-9) and PAK inhibitors (PF3758309, FRAX597) in MM cell lines.
- Assessed effects on cell proliferation, cell cycle regulation (cyclin D), and apoptosis under various conditions (normal, serum starvation).
- Investigated synergistic effects of combined MYC and PAK inhibition.
Main Results:
- MYC inhibition reduced MM cell proliferation by downregulating cyclin D.
- MYC inhibitors induced apoptosis in quiescent MM cells under serum starvation.
- PAK inhibitor PF3758309 showed cytostatic effects at low concentrations and cytotoxicity at high concentrations.
- Combined inhibition of MYC and PAK (KJ-Pyr-9 and FRAX597) demonstrated significant cytotoxic cooperativity.
Conclusions:
- MYC plays a dual role in MM cells, promoting proliferation or survival depending on cellular conditions.
- Targeting MYC can sensitize malignant mesothelioma cells to therapeutic interventions.
- Combining MYC and PAK inhibition represents a promising novel therapeutic strategy for malignant mesothelioma.
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