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| Status |
Public on Jul 02, 2024 |
| Title |
Gene expression changes associated with acquired resistance to anti-EGFR therapy (cetuximab) in colorectal cancer cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Despite the implementation of personalized medicine, patients with metastatic CRC (mCRC) still have a dismal overall survival due to the frequent occurrence of acquired resistance mechanisms thereby leading to clinical relapse. Understanding molecular mechanisms that support acquired resistance to anti-EGFR targeted therapy in mCRC is therefore clinically relevant and key to improving patient outcomes. Here, we observe distinct metabolic changes between cetuximab-resistant CRC cell populations, with in particular an increased glycolytic activity in KRAS-mutant cetuximab-resistant LIM1215 but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 cells have the capacity to recycle glycolysis-derived lactate to sustain their growth capacity. This is associated with an upregulation of the lactate importer MCT1 at both transcript and protein levels. Pharmacological inhibition of MCT1, with AR-C155858, reduces the uptake and oxidation of lactate and impairs growth capacity in cetuximab-resistant LIM1215 cells. This study identifies MCT1-dependent lactate utilization as a clinically actionable, metabolic vulnerability to overcome KRAS-mutant-mediated acquired resistance to anti-EGFR therapy in CRC.
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| Overall design |
To study the metabolic adaptation of CRC cells upon acquired resistance to cetuximab treatment, we used two human colon cancer cell lines LIM1215 and DiFi, initially cetuximab-sensitive (denoted as -S), and for which populations with acquired resistance (-R1 and -R2) had been previously established upon chronic exposure for several months with the drug (Misale et al Nature 2012). While DiFi-R cells harbored EGFR gene copy number reduction and KRAS gene amplification, LIM1215-R cells were reported to display KRAS activating mutations.
We then carried out gene expression profiling analysis using RNA-seq data obtained from cetuximab-resistant (-R1 and -R2) and cetuximab-sensitive (-S) DiFi and LIM1215 CRC cells.
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| Contributor(s) |
Richiardone E, Ambroise J, Boidot R, Bardelli A, Arena S, Corbet C |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Mar 29, 2024 |
| Last update date |
Jul 02, 2024 |
| Contact name |
Jérôme Ambroise |
| E-mail(s) |
jambroise83@gmail.com
|
| Organization name |
Université catholique de Louvain
|
| Department |
Institut de Recherche Expérimentale et Clinique
|
| Street address |
Avenue Hippocrate 54
|
| City |
Woluwé |
| ZIP/Postal code |
1200 |
| Country |
Belgium |
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| Platforms (1) |
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| Samples (18)
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| GSM8179478 |
Cetuximab-sensitive DiFi-S – biol rep 1 [S37] |
| GSM8179479 |
Cetuximab-sensitive DiFi-S – biol rep 2 [S38] |
| GSM8179480 |
Cetuximab-sensitive DiFi-S – biol rep 3 [S39] |
| GSM8179481 |
Cetuximab-resistant DiFi-R1 – biol rep 1 [S40] |
| GSM8179482 |
Cetuximab-resistant DiFi-R1 – biol rep 2 [S41] |
| GSM8179483 |
Cetuximab-resistant DiFi-R1 – biol rep 3 [S42] |
| GSM8179484 |
Cetuximab-resistant DiFi-R2 – biol rep 1 [S43] |
| GSM8179485 |
Cetuximab-resistant DiFi-R2 – biol rep 2 [S44] |
| GSM8179486 |
Cetuximab-resistant DiFi-R2 – biol rep 3 [S45] |
| GSM8179487 |
Cetuximab-sensitive LIM1215-S – biol rep 1 [S46] |
| GSM8179488 |
Cetuximab-sensitive LIM1215-S – biol rep 2 [S47] |
| GSM8179489 |
Cetuximab-sensitive LIM1215-S – biol rep 3 [S48] |
| GSM8179490 |
Cetuximab-resistant LIM1215-R1 – biol rep 1 [S49] |
| GSM8179491 |
Cetuximab-resistant LIM1215-R1 – biol rep 2 [S50] |
| GSM8179492 |
Cetuximab-resistant LIM1215-R1 – biol rep 3 [S51] |
| GSM8179493 |
Cetuximab-resistant LIM1215-R2 – biol rep 1 [S52] |
| GSM8179494 |
Cetuximab-resistant LIM1215-R2 – biol rep 2 [S53] |
| GSM8179495 |
Cetuximab-resistant LIM1215-R2 – biol rep 3 [S54] |
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| Relations |
| BioProject |
PRJNA1093402 |
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