Abstract 3487: Synergy with combined inhibition of upstream EGFR-HER2 and downstream RAF-MEK nodes in breast cancer cells with activating RAS and RAF mutations
Bibliographic record
Abstract
Abstract Targeted therapies have been developed to target a variety of oncogenic proteins implicated in breast cancer. These include epidermal growth factor receptor (EGFR), epidermal growth factor receptor type-2 (HER-2), as well as RAS, RAF and MEK, which together comprise the mitogen activated protein kinase (MAPK) cascade. Herein, we explored the therapeutic efficacy of tyrosine kinase inhibitors of EGFR and HER-2 by testing these inhibitors on a human metastatic breast cancer cell line MDA-MB-231. We also determined whether inhibiting tyrosine kinase receptors correlated with the activity of downstream nodes such as MEK and ERK. We report that EGFR inhibitors potently inhibited the phosphorylation of EGFR, but had no effect on MEK and ERK activity, which were observed to be constitutively active in this cell line. Interestingly, MEK/ERK insensitivity correlated with cytotoxic resistance of MDA-MB-231 cells to EGFR inhibitor treatment. In contrast, targeting both EGFR and HER-2 with a dual EGFR/HER-2 inhibitor Lapatinib resulted in significantly improved cytotoxic effects and a partial reduction in MEK and ERK activity. In comparison to the effects of Lapatinib, targeting RAF with Sorafenib resulted in almost complete abrogation of MEK/ERK signaling activity and enhanced cytotoxicity. Our results are consistent with earlier reports suggesting that MAPK signaling is required for MDA-MB-231 cell survival, consistent with the reported presence of activating RAS and RAF mutations in this cell line. Our data highlight the role of RAS and RAF mutations in the uncoupling of downstream nodes (MEK and ERK) from upstream receptor activation. Lastly, the MEK inhibitor U1026 fully inhibited ERK activity but exhibited poor cytotoxicity. This suggests that MDA-MB-231 cells may circumvent MEK inhibition through upstream survival pathways mediated by activated RAS or RAF. An apparent synergistic cytotoxic effect was noted when combining Sorafenib and U1026. Cytotoxic synergy was also observed when Sorafenib was combined with Lapatinib. These putative synergistic drug combinations show promise in that they could deliver significant cytotoxic effects with reduced doses. We find there is merit in targeting multiple oncogenic nodes concurrently to promote additional therapeutic benefits. This also shows potential use in targeting a broader variety of cancer cells that harbor constitutive MAPK signaling associated with oncogenic RAS or RAF mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3487.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".