Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells
Abstract Therapeutic resistance in cancer emerges from genetic or epigenetic mechanisms that enable cell survival under drug pressure. While several resistance mechanisms to cyclin-dependent kinase inhibitors have been identified, acquired resistance is still a therapeutic challenge. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDK4/6 inhibitor, or Telaglenestat, a glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenestat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growthin vivo, and Telaglenestat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenestat. Our findings reveal that Palbociclib and Telaglenestat combination can effectively forestall acquired resistance to Palbociclib..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 16. Jan. Zur Gesamtaufnahme - year:2024 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Tarrado-Castellarnau, Míriam [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.1101/2024.01.04.574237 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI042105757 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI042105757 | ||
| 003 | DE-627 | ||
| 005 | 20240117090530.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240110s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2024.01.04.574237 |2 doi | |
| 035 | |a (DE-627)XBI042105757 | ||
| 035 | |a (biorXiv)10.1101/2024.01.04.574237 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Tarrado-Castellarnau, Míriam |e verfasserin |0 (orcid)0000-0001-9757-2686 |4 aut | |
| 245 | 1 | 0 | |a Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Therapeutic resistance in cancer emerges from genetic or epigenetic mechanisms that enable cell survival under drug pressure. While several resistance mechanisms to cyclin-dependent kinase inhibitors have been identified, acquired resistance is still a therapeutic challenge. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDK4/6 inhibitor, or Telaglenestat, a glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenestat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growthin vivo, and Telaglenestat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenestat. Our findings reveal that Palbociclib and Telaglenestat combination can effectively forestall acquired resistance to Palbociclib. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Foguet, Carles |0 (orcid)0000-0001-8494-9595 |4 aut | |
| 700 | 1 | |a Tarragó-Celada, Josep |0 (orcid)0000-0001-7322-9736 |4 aut | |
| 700 | 1 | |a Palobart, Marc |4 aut | |
| 700 | 1 | |a Hernández-Carro, Claudia |4 aut | |
| 700 | 1 | |a Perarnau, Jordi |0 (orcid)0000-0003-4276-2479 |4 aut | |
| 700 | 1 | |a Zodda, Erika |0 (orcid)0000-0002-4536-9106 |4 aut | |
| 700 | 1 | |a Polat, Ibrahim H. |4 aut | |
| 700 | 1 | |a Marin, Silvia |0 (orcid)0000-0003-0693-2207 |4 aut | |
| 700 | 1 | |a Suarez-Bonnet, Alejandro |0 (orcid)0000-0003-0296-5896 |4 aut | |
| 700 | 1 | |a Lozano, Juan José |4 aut | |
| 700 | 1 | |a Yuneva, Mariia |0 (orcid)0000-0003-3455-9374 |4 aut | |
| 700 | 1 | |a Thomson, Timothy M. |0 (orcid)0000-0002-4670-9440 |4 aut | |
| 700 | 1 | |a Cascante, Marta |0 (orcid)0000-0002-2062-4633 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2024) vom: 16. Jan. |
| 773 | 1 | 8 | |g year:2024 |g day:16 |g month:01 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2024.01.04.574237 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 16 |c 01 | ||