Abstract 727: Signaling redundancy between EGFR and c-Met: molecular analysis of concurrent inhibition of c-Src and therapeutic potential against prostate cancer
Bibliographic record
Abstract
Abstract Overexpression of growth factor receptors is often associated with advanced stage disease and poor prognosis. Importantly, they can interact with other growth factor receptors and non-receptor tyrosine kinases to promote proliferation, survival, invasion and metastasis. One such signaling crosstalk occurs between the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor (c-Met) that are overexpressed in tumours. The amplification of c-Met in tumours overexpressing EGFR leads to signaling redundancy that causes resistance to EGFR inhibitors. Furthermore, the non-receptor tyrosine kinase c-Src has been shown to synergize with EGFR to promote tumour progression and to mediate the crosstalk between EGFR and c-Met. In order to investigate the mechanisms associated with the EGFR-c-Met-c-Src axis, we sought to identify tumour cell lines responding to the dual-inhibition of EGFR and c-Met and the triple-inhibition of EGFR, c-Met and c-Src using pharmacological inhibitions. We identified two androgen independent prostate cancer cell lines with exquisite sensitivity to EGFR-, c-Met-, c-Src-based combinations: DU145 and PC3. The results showed that the combination of crizotinib (c-Met inhibitor) + gefitinib (EGFR inhibitor) was 2-5-fold more potent (DU145 IC50 = 1.9 μM, PC3 IC50 = 1.9 μM) than the drugs alone in growth inhibition assay. Furthermore, the addition of dasatinib (c-Src inhibitor) to the crizotinib + gefitinib combination further enhanced its potency (DU145 IC50 = 0.003 μM, PC3 IC50 = 0.009 μM). When compared with individual drugs, equieffective combinations of gefitinib with crizotinib showed 2-3-fold superior potency in blocking invasion and inducing cytotoxicity. More importantly, the addition of dasatinib to the crizotinib + gefitinib combination significantly enhanced anti-invasive potency and cell-killing by apoptosis. Analysis of signaling crosstalk between the three kinases showed that dasatinib alone or in combination induced re-phosphorylation of c-Src, EGFR, c-Met and STAT3, particularly after 2-6h of drug exposure. The results indicate that these apparent compensatory re-phosphorylation mechanisms induced by dasatinib did not affect the overall potency of the triple combination. Given the role of these three tyrosine kinases in driving proliferation, invasion and survival of cancer cells, our work suggests that triple-inhibition is required for optimal antitumour activity in cells co-expressing EGFR and c-Met. Citation Format: Suman Rao, Anne-Laure Larroque-Lombard, Ben Allal, Bertrand J. Jean-Claude. Signaling redundancy between EGFR and c-Met: molecular analysis of concurrent inhibition of c-Src and therapeutic potential against prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 727. doi:10.1158/1538-7445.AM2015-727
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".