Cancer Cells Haploinsufficient for ATM Are Sensitized to PARP Inhibitors by <i>MET</i> Inhibition
The <i>MET</i> oncogene encodes a tyrosine kinase (TK) receptor. Its activation protects cells from death but also stimulates DNA damage response by triggering excess replicative stress. Transcriptomic classification of cancer cell lines based on <i>MET</i> expression showed...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/10/5770 |
| Summary: | The <i>MET</i> oncogene encodes a tyrosine kinase (TK) receptor. Its activation protects cells from death but also stimulates DNA damage response by triggering excess replicative stress. Transcriptomic classification of cancer cell lines based on <i>MET</i> expression showed that response to the PARP inhibitor (PARPi) olaparib is poorer in <i>MET</i> overexpressing cell lines. Accordingly, a high <i>MET</i> expressing lung carcinoma cell line was sensitized to PARPi by <i>MET</i> TK inhibition. This was not linked solely to <i>MET</i> overexpression: other <i>MET</i> overexpressing cell lines were biochemically but not functionally responsive to combined inhibition. Moreover, exogenously induced <i>MET</i> overexpression was unable to induce resistance to PARPi. The <i>MET</i> overexpressing cell line, responsive to the combined PARP and <i>MET</i> inhibition, carried a heterozygous mutation of the ATM gene and showed an attenuated response of ATM to PARPi. Among the downstream targets of ATM activation, NuMA was phosphorylated only in response to the combined PARP and <i>MET</i> inhibition. Given the role played by NuMA in mitosis, data show that the latter is affected by <i>MET</i> and PARP inhibition in cells with haploinsufficient ATM. This is important as ATM heterozygous mutation is frequently found in human cancer and in lung carcinomas in particular. |
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| ISSN: | 1661-6596 1422-0067 |