Combined RAF and EGFR inhibition leads to improved in vivo efficacy in BRAF-mutant colorectal cancer. Combined RAF and EGFR inhibition leads to improved.

Slides:

Advertisements

Similar presentations

SCC244 significantly inhibited c-Met–driven tumor growth in cancer CDX models. SCC244 significantly inhibited c-Met–driven tumor growth in cancer CDX models.

Advertisements

Dose-escalation patient response.

Inhibition of FGFR fusion kinase activity repressed tumor growth in a mouse xenograft model. Inhibition of FGFR fusion kinase activity repressed tumor.

Inhibition of CR HCT-116 (A and B) or CR HT-29 cells (B) xenografts in EPA and/or FuOx-treated SCID mice. Inhibition of CR HCT-116 (A and B) or CR HT-29.

CDK4 is required for the hormone-independent growth of ER+ breast cancer cells. CDK4 is required for the hormone-independent growth of ER+ breast cancer.

Treatment with BLU9931 leads to tumor regression in the FGF19-overexpressing PDX-derived xenograft LIXC012. Treatment with BLU9931 leads to tumor regression.

Genetic alterations in the PI3K–PTEN–AKT pathway detected during disease progression and their functional impacts. Genetic alterations in the PI3K–PTEN–AKT.

Supplementary Figure S13

18F-FDG uptake is a noninvasive biomarker of combined MEK–mTORC1 inhibition. 18F-FDG uptake is a noninvasive biomarker of combined MEK–mTORC1 inhibition.

Fig. 6. Combinatorial VCPI and OV M1 treatment is efficacious in vivo and ex vivo. Combinatorial VCPI and OV M1 treatment is efficacious in vivo and ex.

Effects of SC144 on in vivo ovarian tumor.

RAS/RAF pathway-activated ovarian cancer cells exhibit MEK dependence and synergistic induction of apoptosis with combined MEK/AKT inhibition. RAS/RAF.

The STM1787 promoter in Salmonella is rapidly activated in vivo by the tumor microenvironment. The STM1787 promoter in Salmonella is rapidly activated.

Fig. 4. Antitumor efficacy of ERY974 against various cancer types.

Inhibition of FGFR signaling and tumor growth in SNU-16 xenograft model by administration of E7090. Inhibition of FGFR signaling and tumor growth in SNU-16.

PDGFRβ is dispensable for EGFRvIII-driven GBM growth but is required for the optimal growth of EGFR-inhibited tumors. PDGFRβ is dispensable for EGFRvIII-driven.

Volume 23, Issue 1, Pages (January 2013)

Treatment with BLU9931 leads to tumor regression in the FGF19-amplified Hep 3B liver cancer model. Treatment with BLU9931 leads to tumor regression in.

In vivo efficacy of gemcitabine and MK-1775.

The EGF receptor confers BRAF inhibitor resistance in BRAF-mutant melanoma cells. The EGF receptor confers BRAF inhibitor resistance in BRAF-mutant melanoma.

Merlin-deficient RAS-mutant cells and murine PDTCs are more sensitive to MEK inhibition. Merlin-deficient RAS-mutant cells and murine PDTCs are more sensitive.

Antiestrogen Fulvestrant Enhances the Antiproliferative Effects of Epidermal Growth Factor Receptor Inhibitors in Human Non–Small-Cell Lung Cancer Edward.

A, left: indicated MEFs were transfected as described in the Methods section. A, left: indicated MEFs were transfected as described in the Methods section.

Regulated P124SMEK1 expression cannot alter p-ERK levels or sensitivity to BRAF or MEK inhibition in V600EBRAF melanoma cell lines. Regulated P124SMEK1.

NrasG12D induces CNS tumors in mice.

BRAF amplification causes clinical acquired resistance to combined RAF/EGFR inhibition. BRAF amplification causes clinical acquired resistance to combined.

Signaling induced by BRAF L597R and L597S is sensitive to BRAF and MEK inhibitors. Signaling induced by BRAF L597R and L597S is sensitive to BRAF and MEK.

Core promoter methylation in mediators of adipogenesis.

Role of HER2 in mediating acquired resistance to EGFR inhibition.

Chloroquine (CQ) improves tumor cell kill when used in combination with vemurafenib and chemotherapy in BRAFV600E-mutant cells. Chloroquine (CQ) improves.

Confirmation of synergy and cytotoxicity of genotype-selective drug pairs. Confirmation of synergy and cytotoxicity of genotype-selective drug pairs. A,

Combined HDAC and mTOR inhibitors kill NF1-mutant malignancies in vitro and in vivo. Combined HDAC and mTOR inhibitors kill NF1-mutant malignancies in.

Volume 22, Issue 5, Pages (November 2012)

IL-6 signaling affects response to erlotinib in head and neck (HNSCC) cells. IL-6 signaling affects response to erlotinib in head and neck (HNSCC) cells.

Antitumor efficacy of PI3K inhibitor NVP-BKM120 alone and in combination with olaparib. Antitumor efficacy of PI3K inhibitor NVP-BKM120 alone and in combination.

CO-1686 does not inhibit WT EGFR signaling in vivo and is active in EGFR-mutant transgenic mouse lung cancer models. CO-1686 does not inhibit WT EGFR signaling.

Fig. 6 RUNX/CBFB interaction inhibitor, Ro5-3335, significantly decreases mouse neurofibroma growth in vivo. RUNX/CBFB interaction inhibitor, Ro5-3335,

GR cells are dependent upon sustained CDC25C signaling as pharmacologic or genetic inhibition of CDC25C induce synthetic lethality. GR cells are dependent.

The SFKs confer BRAF inhibitor resistance in BRAF-mutant melanoma cells. The SFKs confer BRAF inhibitor resistance in BRAF-mutant melanoma cells. A, phospho-protein.

PRIMA-1Met inhibits the growth of multiple myeloma tumors with mutant p53 in vivo. PRIMA-1Met inhibits the growth of multiple myeloma tumors with mutant.

Discovery of Gö6976-related potent reversible EGFR T790M inhibitors.

Pharmacological targeting of CDs promotes response to KRASG12C inhibition in vivo. Pharmacological targeting of CDs promotes response to KRASG12C inhibition.

Targeting HR via CDK inhibition resensitizes recurrent cultures to temozolomide (TMZ). Targeting HR via CDK inhibition resensitizes recurrent cultures.

Five-day exposure to decitabine (DAC) sensitizes cells to doxorubicin (Doxo). Five-day exposure to decitabine (DAC) sensitizes cells to doxorubicin (Doxo).

Establishment of 12 PDX from BRAF inhibitor–progressed patients.

CRA inhibits the growth of human tumor xenografts in vivo.

NT157 treatment inhibits LNCaP xenograft growth and delays castration-resistant progression. NT157 treatment inhibits LNCaP xenograft growth and delays.

Activity of a chemically modified miR-21 inhibitor in human bladder cancer xenografts. Activity of a chemically modified miR-21 inhibitor in human bladder.

KRAS mutation leads to resistance to combined RAF/EGFR and RAF/MEK inhibition. KRAS mutation leads to resistance to combined RAF/EGFR and RAF/MEK inhibition.

MEK1F53L mutation drives clinical acquired resistance to combined RAF/MEK inhibition. MEK1F53L mutation drives clinical acquired resistance to combined.

Lapatinib cooperates with PLX4032 to inhibit BRAF-mutant thyroid cancer cell growth. Lapatinib cooperates with PLX4032 to inhibit BRAF-mutant thyroid cancer.

Differential effects of the RAF inhibitor PLX4032 in BRAF-mutant melanoma, thyroid, and colorectal cancer cell lines. Differential effects of the RAF inhibitor.

MGA271 exhibits potent in vivo antitumor activity toward tumor cell carcinoma xenografts. MGA271 exhibits potent in vivo antitumor activity toward tumor.

TAE-684 effectively inhibits the growth of H3122 in vivo.

Proliferation of TA3-Ha and TA3-St cells in vitro and in vivo.

PDL192 and inhibit the growth of xenograft tumors.

Ganetespib suppresses tumor growth and extends survival in ALK+ NSCLC xenografts. Ganetespib suppresses tumor growth and extends survival in ALK+ NSCLC.

Heterogeneous resistance mechanisms develop in response to W+T combination treatment in the EGFRL858R/T790M genetically engineered mice. Heterogeneous.

GCS-100 selectively kills KRAS-addicted lung tumors.

Fig. 6. Combinatorial VCPI and OV M1 treatment is efficacious in vivo and ex vivo. Combinatorial VCPI and OV M1 treatment is efficacious in vivo and ex.

Ceritinib is a potent ALK inhibitor in crizotinib-naïve models.

EPHA2 inhibitors inhibit phosphorylation of AKT and ERK, arrest cell cycle at G0–G1, and induce apoptosis in both vemurafenib (VEM)-sensitive and VEM-resistant.

FGFR2 amplification in primary human gastric tumors predicts for response to NVP-BGJ398. FGFR2 amplification in primary human gastric tumors predicts for.

In vivo effect of KIN-193 on PTEN-deficient tumors.

BH3-targeted inhibitors drive specific resistance in human cell lines, which can be overcome with alternating or combining inhibitors. BH3-targeted inhibitors.

Curative effect of W+T treatment in vivo.

AMG 176 exhibits robust single-agent activity in vivo.

Therapeutic strategies for different classes of BRAF and MEK mutations

Wnt5A and ROR2 contribute to intrinsic resistance to BRAF inhibitors.

Combining IGF1R inhibitors with MEK or RAF inhibitors enhances the differential impact upon mutant KRAS cells. Combining IGF1R inhibitors with MEK or RAF.

Presentation transcript:

Combined RAF and EGFR inhibition leads to improved in vivo efficacy in BRAF-mutant colorectal cancer. Combined RAF and EGFR inhibition leads to improved in vivo efficacy in BRAF-mutant colorectal cancer. A, BRAF-mutant colorectal cancer xenografts derived from HT-29 and WiDr cells were treated with vehicle only (CON), vemurafenib only (VEM, 75 mpk twice daily), erlotinib (ERL, 100 mpk daily), or both inhibitors (VEM/ERL) in combination for 21 days. Average percent change in tumor volume relative to initial tumor volume is shown. Error bars represent SEM. **P < 0.001 for combined vemurafenib/erlotinib vs. all other treatment groups. B, waterfall plots showing the percent change in volume (relative to initial tumor volume) for the individual tumors in each treatment group. C, tumor tissue from HT-29 xenografts treated for 3 days as indicated was evaluated by IHC for P-ERK and a marker of cell proliferation (Ki67). Tumors were harvested 4 hours after dosing on day 3. D, levels of P-EGFR were assessed in human BRAF-mutant colorectal cancers (CRC) and melanomas by IHC. Representative examples are shown. Colorectal cancer cases with the lowest (C3) and highest (C7) P-EGFR levels are shown. A total of 60% of BRAF-mutant colorectal cancers (n = 10) exhibited high levels of P-EGFR, whereas only 18% of BRAF-mutant melanomas (n = 11) exhibited high levels of P-EGFR (P < 0.05). Ryan B. Corcoran et al. Cancer Discovery 2012;2:227-235 ©2012 by American Association for Cancer Research