AXL is not necessary for maintenance of intrinsic resistance.

Slides:

Advertisements

Similar presentations

Functional role of Pak1/Erk signaling in Rac-related diseases Daniela Araiza-Olivera, Jennifer Rhodes, and Jonathan Chernoff FOX CHASE CANCER CENTER, 333.

Advertisements

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

MAPK pathway inhibitors.

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

PI3K isoform–selective inhibitors and PTEN induction decrease ERK phosphorylation. PI3K isoform–selective inhibitors and PTEN induction decrease ERK phosphorylation.

Combined inhibition of MAP kinase and KIT signaling destabilizes ETV1 protein and results in enhanced growth suppression of human GIST cells. Combined.

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

AKT dependence of ovarian cancer cell lines.

Kavitha Gowrishankar, Stephanie Snoyman, Gulietta M. Pupo, Therese M

by Reuben Kapur, Ryan Cooper, Lei Zhang, and David A. Williams

NF1 downregulation activates MAPK pathway signaling.

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.

Volume 29, Issue 3, Pages (March 2016)

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

A genome-wide RNAi pooled screen identifies NF1 as a key determinant of RAF inhibitor sensitivity in melanoma cells. A genome-wide RNAi pooled screen identifies.

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.

p38 MAPK activation is required for phosphorylation of Akt at Ser473.

BRAF inhibitor-resistant BRAF-mutant melanoma cells show increased invasion and metastatic potential. BRAF inhibitor-resistant BRAF-mutant melanoma cells.

AMPK induces VEGF-A production by upregulating ERK signaling.

Pharmacologically inhibiting BRAF/ERK and CDK4 restores APCFZR1 E3 ligase activity. Pharmacologically inhibiting BRAF/ERK and CDK4 restores APCFZR1 E3.

A and B, CO-1686–resistant NCI-H1975 cell clones, COR1-1 and COR10-1 display a reduced dependence on EGFR signaling for survival. A and B, CO-1686–resistant.

Volume 8, Issue 4, Pages (October 2005)

PERK signaling is constitutively activated upon EMT and promotes malignancy. PERK signaling is constitutively activated upon EMT and promotes malignancy.

CEP55 is a downstream effector of MAPK signaling

Volume 22, Issue 5, Pages (November 2012)

Computed tomographic images from a patient with BRAFL597S-mutant metastatic melanoma responding to therapy with the MEK inhibitor TAK-733. Computed tomographic.

P38 activation mediates chronic insulin-induced IRS1 and IRS2 degradation and is involved in myocardial insulin resistance in vitro. p38 activation mediates.

TNFα is an important survival and growth signal for melanoma.

Aβ-mediated Ras-MAPK signaling and Cyclin D1 expression in B103 cells are dependent on APP expression and can be reversed with MEK or Ras inhibition. Aβ-mediated.

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

Gramicidin A (GA) decreases HIF protein expression in RCC cells.

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.

Effect of LY on phosphorylation of various MAP kinase substrates in HeLa cells in vitro. Effect of LY on phosphorylation of various MAP kinase.

Oncogenic indel hotspots.

Radiosensitization by combined Wee1 and PARP inhibition.

Inhibition of stress-associated MAPK signaling attenuates SASP expression in CAFs. A, N-CAFs were treated with 100 nmol/L GEM plus DMSO or the above-listed.

Sensor siRNAs can be used in high-order combinations.

Down-regulation of the erbB-2 receptor by trastuzumab decreases Akt kinase activation but not MAPK activation. Down-regulation of the erbB-2 receptor by.

Effect of other nucleoside analogues on p38 MAPK phosphorylation levels. Effect of other nucleoside analogues on p38 MAPK phosphorylation levels. A, MM.1S.

Expression of versican promoted breast cancer cell self-renewal through enhanced EGFR/AKT/GSK-3β (S9P) signals. Expression of versican promoted breast.

The effect of IAA and glycyrrhizin (Gc) on growth of human melanoma cells. The effect of IAA and glycyrrhizin (Gc) on growth of human melanoma cells. A,

PPP2R2A overexpression rescues the miR-21–induced biological effects in bladder cancer cells. PPP2R2A overexpression rescues the miR-21–induced biological.

Effect of GSK3β inhibition on cell survival and proliferation of glioblastoma cells. Effect of GSK3β inhibition on cell survival and proliferation of glioblastoma.

ERK reactivation following EGFR TKI treatment.

Changes in signal transduction pathway induced by gefitinib.

HES1-dependent activation of SRC/STAT3 pathway is mediated by transcription-independent mechanism. HES1-dependent activation of SRC/STAT3 pathway is mediated.

The combination of trastuzumab and SU11274 abrogate Akt phosphorylation. The combination of trastuzumab and SU11274 abrogate Akt phosphorylation. Serum-starved.

EMT alters activation of AKT and serum-independent proliferation.

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

Establishment of transcriptional class distinction in melanocytes.

MAPK/ERK signaling regulates TLR4 gene expression in response to BRAFV600E. MAPK/ERK signaling regulates TLR4 gene expression in response to BRAFV600E.

Induction of apoptosis by statins in NB4 cells and NB4 variant cell lines. Induction of apoptosis by statins in NB4 cells and NB4 variant cell lines. A,

KRASG12D- and BRAFV600E-induced survival in PDECs requires IGF1R signaling. KRASG12D- and BRAFV600E-induced survival in PDECs requires IGF1R signaling.

The effects of AZD1775 and olaparib on DNA damage response signaling.

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.

AKT activation in HCC2429 is SRC- but not Notch-dependent.

Validation of MYC-driven drug responses.

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

Crizotinib-resistant NPM-ALK mutants retain sensitivity to ganetespib.

HER2 and PI3K-targeted therapies result in FOXO3a-mediated feedback upregulation of HER3 and IGF1R and provide an escape from PI3K pathway inhibition.

MTOR kinase inhibition–induced reactivation of AKT substrates is HER2 and PI3K dependent. mTOR kinase inhibition–induced reactivation of AKT substrates.

An overview of the MAPK signaling pathway with points of therapeutic intervention indicated. An overview of the MAPK signaling pathway with points of therapeutic.

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.

T3 or T4 induces MAPK activation in myeloma cells.

Mechanism of ERM protein–dependent CD44 cleavage.

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.

MITF-low/NF-κB–high transcriptional class is present and associated with resistance to MAPK pathway inhibition in human tumors. MITF-low/NF-κB–high transcriptional.

Presentation transcript:

AXL is not necessary for maintenance of intrinsic resistance. AXL is not necessary for maintenance of intrinsic resistance. A, effects of AXL overexpression on survival of drug-sensitive BRAFV600-mutant melanoma cell lines following 4-day treatment with PLX4720 (RAFi, 2 μmol/L), AZD6244 (MEKi, 200 nmol/L), PLX4720 + AZD6244, or VTX11E (ERKi, 2 μmol/L). MEK1 is a negative control; RAF1 is a positive control for RAFi resistance. Data are mean ± standard deviation. Asterisks beneath graph indicate P < 0.01 (two-tailed t test) relative to the same cell line, expressing MEK1, and treated with the same drug. B, effects of AXL overexpression on phosphorylation of AKT and maintenance of ERK phosphorylation following overnight treatment with MAPK pathway inhibitors. D, DMSO; P, 2 μmol/L PLX4720; A, 200 nmol/L AZD6244; PA, PLX4720 + AZD6244; and E, VTX11E, 2 μmol/L. MEK1 is a negative control; RAF1 is a positive control for pERK reactivation following RAFi treatment. C, effects of AXL inhibitors on induction of pAKT and rescue of pERK following AXL overexpression. R428, 500 nmol/L; XL184, 3 μmol/L; XL880, 100 nmol/L; in the presence or absence of 2 μmol/L PLX4720. shAXL is a positive control. D, effects of AXL inhibitors on pAKT and pERK levels in intrinsically resistant cell lines in the presence or absence of PLX4720. E, effects of AXL inhibitors on intrinsic resistance to PLX4720. David J. Konieczkowski et al. Cancer Discovery 2014;4:816-827 ©2014 by American Association for Cancer Research