Kui Wang May 6th, 2017.

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Presentation transcript:

Kui Wang May 6th, 2017

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

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

Synthetic-lethal interactions

Pooled negative-selection RNA interference screening

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.

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.

FGFR1 mediates adaptive drug resistance to trametinib

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

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

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.

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

FGFR1 inhibition enhances trametinib effects Ponatinib: 普纳替尼

FGFR1 inhibition enhances trametinib effects

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

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

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.

In vivo effects of MEK/FGFR1 inhibition

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

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

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

Thank You