Abstract A31: eIF4F links translation to energy stress response in cancer
Bibliographic record
Abstract
Abstract Protein synthesis is one of the most energy consuming process in the cell. Oncogenic kinases (e.g. EGFR/HER2, BCR/ABL and BRAF) play a central role in reprogramming translation and energy metabolism in neoplasia, whereby cancer cells must provide sufficient ATP to support increased levels of protein synthesis required for neoplastic growth. The downstream mechanisms that link translational machinery and energy homeostasis in cancer, however, remain largely unknown. We found that widely used anti-diabetics (biguanides) abrogate adaptations to EGFR/HER2 inhibitor-induced energetic stress, which results in synergistic anti-neoplastic effects both in vitro and in vivo. In turn, breast cancer cells in which 4E-BP1/2 expression was abrogated by CRISPR were partially resistant to the combination of EGFR/HER2 inhibitors and biguanides. This was paralleled by the inability of the drugs to inhibit the eIF4F complex assembly and translation of mRNAs encoding important metabolic regulators including those involved in serine biogenesis (PHGDH, PSAT1) and one carbon metabolism (MTHFD1L). Comparable results were observed when BRAF and BCR/ABL inhibitors were combined with biguanides, which suggests that translational regulation of metabolic genes via the mTORC1/4E-BE/eIF4E pathway plays a major role in energy stress response in cancer. Together our findings demonstrate that the eIF4F complex is an important mediator of metabolic adaptation in response to the combination of biguanides and clinically-used kinase inhibitors and suggest that the efficiency of such anti-cancer strategies are dependent on the integrity of the translation initiation machinery. Citation Format: Laura Hulea, Marie Cargnello, Simon-Pierre Gravel, Young Im, Shannon McLaughlan, Yunhua Zhao, Jenna Ching, Yutian Cai, Ola Larsson, Michael Ohh, Josie Ursini-Siegel, Julie St-Pierre, Michael Pollak, Ivan Topisirovic. eIF4F links translation to energy stress response in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A31.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".