MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive Tumourigenesis
Targeted therapies for <i>MET</i> exon 14-skipping (<i>METΔe</i><i>x14</i>)-driven lung cancers have generated some promising results but response rates remain below that seen for other kinase-driven cancers. One strategy for improving treatment outcomes is to emp...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/6/1378 |
| _version_ | 1797472554937483264 |
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| author | Daniel Lu Amy Nagelberg Justine LM Chow Yankuan T Chen Quentin Michalchuk Romel Somwar William W. Lockwood |
| author_facet | Daniel Lu Amy Nagelberg Justine LM Chow Yankuan T Chen Quentin Michalchuk Romel Somwar William W. Lockwood |
| author_sort | Daniel Lu |
| collection | DOAJ |
| description | Targeted therapies for <i>MET</i> exon 14-skipping (<i>METΔe</i><i>x14</i>)-driven lung cancers have generated some promising results but response rates remain below that seen for other kinase-driven cancers. One strategy for improving treatment outcomes is to employ rational combination therapies to enhance the suppression of tumour growth and delay or prevent the emergence of resistance. To this end, we profiled the transcriptomes of MET-addicted lung tumours and cell lines and identified the RAS-mitogen-activated protein kinase (MAPK) pathway as a critical effector required for METΔex14-dependent growth. Ectopic expression of <i>MET</i> in an isogenic cell line model showed that overexpression of the mutant MET receptor led to higher levels of MAPK phosphorylation and nuclear import, resulting in increased expression and phosphorylation of nuclear MAPK targets. In comparison, other known MET effectors were unaffected. Inhibition of this pathway by <i>KRAS</i> knockdown in MET-addicted cells in vitro led to decreased viability in only the <i>METΔex14</i>-mutant cells. Conversely, decoupling RAS-MAPK axis, but not other effector pathways, from MET activity via the introduction of constitutively active mutants conferred resistance to MET inhibitors in vitro. Our results suggest that aberrant hyperactivity of the MET receptor caused by the exon 14-skipping mutation does not uniformly upregulate all known downstream effectors, rather gaining a predilection for aberrantly activating and subsequently relying on the RAS-MAPK pathway. These findings provide a rationale for the co-targeting of the RAS-MAPK pathway alongside MET to prolong therapeutic response and circumvent resistance to improve patient survival. |
| first_indexed | 2024-03-09T20:03:05Z |
| format | Article |
| id | doaj.art-9d7dbb149afe49e090f93cd07c88b12f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:03:05Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-9d7dbb149afe49e090f93cd07c88b12f2023-11-24T00:40:05ZengMDPI AGCancers2072-66942022-03-01146137810.3390/cancers14061378MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive TumourigenesisDaniel Lu0Amy Nagelberg1Justine LM Chow2Yankuan T Chen3Quentin Michalchuk4Romel Somwar5William W. Lockwood6Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USADepartment of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaTargeted therapies for <i>MET</i> exon 14-skipping (<i>METΔe</i><i>x14</i>)-driven lung cancers have generated some promising results but response rates remain below that seen for other kinase-driven cancers. One strategy for improving treatment outcomes is to employ rational combination therapies to enhance the suppression of tumour growth and delay or prevent the emergence of resistance. To this end, we profiled the transcriptomes of MET-addicted lung tumours and cell lines and identified the RAS-mitogen-activated protein kinase (MAPK) pathway as a critical effector required for METΔex14-dependent growth. Ectopic expression of <i>MET</i> in an isogenic cell line model showed that overexpression of the mutant MET receptor led to higher levels of MAPK phosphorylation and nuclear import, resulting in increased expression and phosphorylation of nuclear MAPK targets. In comparison, other known MET effectors were unaffected. Inhibition of this pathway by <i>KRAS</i> knockdown in MET-addicted cells in vitro led to decreased viability in only the <i>METΔex14</i>-mutant cells. Conversely, decoupling RAS-MAPK axis, but not other effector pathways, from MET activity via the introduction of constitutively active mutants conferred resistance to MET inhibitors in vitro. Our results suggest that aberrant hyperactivity of the MET receptor caused by the exon 14-skipping mutation does not uniformly upregulate all known downstream effectors, rather gaining a predilection for aberrantly activating and subsequently relying on the RAS-MAPK pathway. These findings provide a rationale for the co-targeting of the RAS-MAPK pathway alongside MET to prolong therapeutic response and circumvent resistance to improve patient survival.https://www.mdpi.com/2072-6694/14/6/1378lung cancertargeted therapiesHepatocyte Growth Factor Receptorsplice-site mutationsRAS |
| spellingShingle | Daniel Lu Amy Nagelberg Justine LM Chow Yankuan T Chen Quentin Michalchuk Romel Somwar William W. Lockwood MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive Tumourigenesis Cancers lung cancer targeted therapies Hepatocyte Growth Factor Receptor splice-site mutations RAS |
| title | MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive Tumourigenesis |
| title_full | MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive Tumourigenesis |
| title_fullStr | MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive Tumourigenesis |
| title_full_unstemmed | MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive Tumourigenesis |
| title_short | MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive Tumourigenesis |
| title_sort | met exon 14 splice site mutations preferentially activate kras signaling to drive tumourigenesis |
| topic | lung cancer targeted therapies Hepatocyte Growth Factor Receptor splice-site mutations RAS |
| url | https://www.mdpi.com/2072-6694/14/6/1378 |
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