1. Kui Wang
May 6th, 2017

2. Memorial Sloan Kettering Cancer Center
Scott W. Lowe
Memorial Sloan Kettering Cancer Center
Research Focus:
Tumor-suppressor gene networks that control apoptosis and senescence

3. Background
Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology.
KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents.
To identifying combination targets for trametinib, a MEK inhibitor which acts downstream of KRAS to suppress signalling through MAPK cascade.
Trametinib: 曲美替尼

4. Synthetic-lethal interactions

5. Pooled negative-selection RNA interference screening

6. Screen to identify trametinib sensitizers
BRAF, CRAF, ERK2, and FGFR1 as the top candidates
Cell competition assays: shRNA-transduced cells were mixed with non-transduced cells (8:2).
Trametinib has superior pharmacological properties compared with other MEK inhibitors
because it impairs feedback reactivation of ERK.

7. Suppression of MAPK signalling effectors sensitizes
KRAS-mutant lung cells to trametinib.
ERK inhibitor SCH772984
Marked dependency of KRAS-mutant tumours on the MAPK signalling pathway.

8. FGFR1 mediates adaptive drug resistance to trametinib

9. FGFR1 mediates adaptive drug resistance to trametinib
FGFR1 shRNAs did not inhibit the proliferation of KRAS-mutant lung cancer, but displayed synergistic inhibitory effects when combined with trametinib

10. FGFR1 mediates adaptive drug resistance to trametinib
FGFR1 knockdown had little impact on trametinib sensitivity in KRAS wild-type lung cancer cells

11. FGFR1 mediates adaptive drug resistance to trametinib
FGFR1 shRNAs synergized with trametinib in two KRAS-mutant pancreatic cancer cell lines, they showed little activity in trametinib-treated KRAS-mutant colorectal lines.

12. FGFR1 mediates adaptive drug resistance to trametinib
This genotype and tissue specificity correlated with the ability of trametinib to trigger FRS2 phosphorylation when applied as a single agent

13. FGFR1 inhibition enhances trametinib effects
Ponatinib: 普纳替尼

14. FGFR1 inhibition enhances trametinib effects

15. FGFR1 inhibition enhances trametinib effects
BGJ398, AZD4547: FGFR inhibitors
Sensitivity to the combination of trametinib and FGFR inhibition correlated with the degree of pFRS2 induction after trametinib treatment

16. FGFR1 inhibition enhances trametinib effects
H460 cells harbours an activating mutation in the p110α catalytic
subunit of PI3K

17. FGFR1 inhibition enhances trametinib effects
ERK inhibitor SCH772984
Afatinib: EGFR/ERBB2 inhibitor
The combined ability of ponatinib to impact reactivation of the MAPK and PI3K pathways contributes to its combinatorial activity in KRAS-mutant lung cancer cells.

18. In vivo effects of MEK/FGFR1 inhibition

19. In vivo effects of MEK/FGFR1 inhibition
3 weeks
7 weeks

20. In vivo effects of MEK/FGFR1 inhibition
Organoid-based, transplantable model of KrasG12D-driven pancreatic cancer

21. In vivo effects of MEK/FGFR1 inhibition
Patients having KRAS-mutant lung adenocarcinomas

22. Thank You