Defining the role of different KRAS effectors in the initiation and progression of lung cancer
Bibliographic record
Abstract
Lung cancer is currently the most deadly malignancy in Canada, accounting for 27% of all cancer-related deaths. Over 70% of patients with non-small cell lung cancer (NSCLC) are diagnosed at a late stage, with a 5-year survival below 10%. In NSCLC, the two oncogenes that are most frequently mutated are the EGFR and KRAS genes. While targeted therapies have been developed for patients with EGFR mutations, oncogenic KRAS mutations are so far not druggable. KRAS is a small GTPase that acts as an on/off switch to activate multiple signalling pathways, including the PI3K/Akt pathway, the Raf-Mek-Erk pathway and the RalGDS/Ral pathway. In the BrafCA mouse model of lung tumourigenesis, it was shown that the Cre-mediated expression of BrafV600E, activating the Raf-Mek-Erk pathway, causes the formation of adenomas that undergo widespread senescence at the benign stage. However, oncogenic KRAS mutations in mice cause adenocarcinomas, which suggests that other pathways activated by KRAS cooperate with sustained RAF-MEK-ERK signalling to bypass the oncogene-induced senescence proliferation arrest. To elucidate which pathways may cooperate with the Raf-Mek-Erk pathway to lead to lung adenocarcinomas, I created four effector domain mutants of KRASV12 (S35, G37, E38 and C40). The S35 and E38 mutants bind to Raf proteins but not PI3K or RalGDS; the G37 mutant binds to RalGDS and not Raf or PI3K and the C40 mutant is specific to PI3K. I designed lentiviral vectors that code for the KRAS mutants (V12, V12/S35, V12/G37, V12/E38 or V12/C40), or eGFP as a negative control, bicistronically with the Cre recombinase. These lentiviruses were used to infect BrafCA/+ and wild-type mice. The biggest tumours seen in BrafCA/+ mice received the KRASV12 virus, followed closely by KRASV12/C40, suggesting that the PI3K and Raf-Mek-Erk pathways cooperate to increase tumour growth. There was a significant decrease in tumour penetrance in all conditions where any KRAS mutant was present compared to the eGFP control, suggesting that KRAS may directly activate effectors with tumour suppressive functions. Moreover, tumours in wild-type mice were only seen with KRASV12 expression.
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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 | 0.001 | 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 | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".