Cetuximab and Savolitinib Treatment of Ras Wild-Type Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2204283 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient’s tumor. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. However, among the various KRAS mutations, the G13D mutation behaves differently; for unknown reasons, CRC patients with the KRAS G13D mutation (also written KRASG13D) appear to benefit from the EGFR-blocking antibody cetuximab. Controversy surrounds this observation, because it appears to contradict the well-established mechanisms of EGFR signaling and of RAS mutations. Here, we identified a systems-level, mechanistic basis that explains why KRASG13D cancers respond to EGFR inhibition. We first investigated the problem with a computational model of RAS signaling, which unexpectedly revealed that the known biophysical differences between the three most common KRAS mutant proteins are sufficient to generate different sensitivities to inhibition. Computation and experimentation together revealed a non-intuitive, mutant-specific dependency of wild-type RAS activation by EGFR that is determined by the interaction strength between KRAS and the tumor suppressor neurofibromin (NF1). KRAS mutants that strongly interact with NF1 drive wild-type RAS activation in an EGFR independent manner through competitive inhibition of NF1, whereas KRAS G13D cells remain dependent upon EGFR for wild-type Ras activation because they cannot competitively inhibit NF1 due to a weak interaction between these two proteins. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine and can help identify patients for selective therapeutic strategies.
2020-05-27 | PXD014755 | Pride
Project description:Recent preclinical studies suggest that combining MEK and MDM2 inhibition synergize to induce apoptosis in RAS/BRAF-mutant and TP53 wild-type CRC models. In vitro, in RKO cell lines (poorly differentiated colon carcinoma cell line resistant to single agent targeting MDM2 and MEK and BRAF inhibition), the MDM2 plus MEK inhibitor combination generated a synergistic increase in apoptotic index. In vivo, in mice harboring human RKO colon tumor xenografts the combination of MDM2 plus MEK inhibition elicited 93% decreases in tumor volume.
This trial is to conduct a single-center, Phase 1 dose escalation study of trametinib combined with HDM201 (a HDM2 inhibitor) in patients with advanced/metastatic RAS/RAF mutant and TP53 wt CRC.
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Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>
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Project description:Amplification and activation of the Met receptor tyrosine kinase occurs up to 23% of gastric cancers, suggesting that Met is a therapeutic target in these cancers. However, the steady-state signaling events that occur during chronic Met activation, and mechanisms for resistance to Met small-molecule inhibitors, are poorly understood. Here we show that multiple gastric cancer cell lines harboring MET amplifications are dependent on Met signaling for proliferation and anchorage-independent growth. In these cells, short-term inhibition of Met leads to coordinated changes in gene expression; these include a rapid loss in expression of immediate-early genes, followed by decreased expression of genes involved in cell cycle and proliferation. Activation of Ras-Erk, PI3K-Akt and STAT3 pathways is attenuated by acute Met inhibition. STAT3 inhibition alone, but not individual inhibition of Mek or Akt, is sufficient to abrogate Met-dependent growth of these cells. However, following chronic Met inhibition, reactivation of Mek-dependent Erk phosphorylation occurs even in the presence of Met inhibitor corresponding with a downregulation of Erk negative regulators DUSP4/6. This provides a mechanism for the emergence of drug resistance. Our findings provide insights into innate resistance to a small-molecule Met inhibitor and highlight rational combination therapies that could be evaluated in clinical trials. Time series experiment, four cell lines, 2 treatments
2014-05-19 | E-GEOD-54532 | biostudies-arrayexpress
Project description:Amplification and activation of the Met receptor tyrosine kinase occurs up to 23% of gastric cancers, suggesting that Met is a therapeutic target in these cancers. However, the steady-state signaling events that occur during chronic Met activation, and mechanisms for resistance to Met small-molecule inhibitors, are poorly understood. Here we show that multiple gastric cancer cell lines harboring MET amplifications are dependent on Met signaling for proliferation and anchorage-independent growth. In these cells, short-term inhibition of Met leads to coordinated changes in gene expression; these include a rapid loss in expression of immediate-early genes, followed by decreased expression of genes involved in cell cycle and proliferation. Activation of Ras-Erk, PI3K-Akt and STAT3 pathways is attenuated by acute Met inhibition. STAT3 inhibition alone, but not individual inhibition of Mek or Akt, is sufficient to abrogate Met-dependent growth of these cells. However, following chronic Met inhibition, reactivation of Mek-dependent Erk phosphorylation occurs even in the presence of Met inhibitor corresponding with a downregulation of Erk negative regulators DUSP4/6. This provides a mechanism for the emergence of drug resistance. Our findings provide insights into innate resistance to a small-molecule Met inhibitor and highlight rational combination therapies that could be evaluated in clinical trials.
2014-05-19 | GSE54532 | GEO
Project description:We have previously shown that some gefitinib insensitive head and neck squamous cell carcinoma (HNSCC) cell lines exhibit dominant autocrine fibroblast growth factor receptor (FGFR) signaling. Herein, we deployed a whole genome loss-of-function screen to identify genes whose knockdown potentiated the inhibitory effect of the FGFR inhibitor, AZ12908010, in HNSCC cell lines. Three HNSCC cell lines expressing a genome-wide shRNA library were treated with AZ8010 and the abundance of shRNA sequences was assessed by deep sequencing. Synthetic lethal hits were validated through use of specific inhibitors and independent shRNAs. We found that multiple alternate receptors provided protection from FGFR inhibition, including the receptor tyrosine kinases (RTKs), epidermal growth factor receptor 2 (ERBB2) and hepatocyte growth factor receptor (MET). We showed that specific knockdown of either ERBB2 or MET in combination with FGFR inhibition led to increased inhibition of growth relative to FGFR tyrosine kinase inhibitor (TKI) treatment alone. These results were confirmed using specific small molecule inhibitors of either ERBB family members or MET. Moreover, the combination of FGFR, MET and ERBB family inhibitors showed the largest inhibition of growth as compared to the double combinations. These results reveal a role for alternate RTKs in maintaining pro-growth and survival signaling in HNSCC cells in the setting of FGFR inhibition. Thus, improved therapies for HNSCC patients could involve rationally designed combinations of TKIs targeting FGFR, ERBB family members and MET. Using a genome-wide shRNA library in combination with deep sequencing, we screened for gene targets that were synthetic lethal with the FGFR inhibitor, AZ12908010 in HNSCC cells. Three HNSCC cell lines were screened in triplicate and the abundance of shRNA sequences in drug treated cells was compared to control treated cells.
2013-05-03 | E-GEOD-39305 | biostudies-arrayexpress
Project description:Targeted therapies for MET exon 14-skipping (METΔex14)-driven lung cancers have generated some promising results but response rates remain below that seen for other kinase-driven cancers. One strategy for improving treatment outcomes is to employ rational combination therapies to enhance the suppression of tumour growth and delay or prevent the emergence of resistance. To this end, we profiled the transcriptomes of MET-addicted lung tumours and cell lines and identified the RAS-mitogen-activated protein kinase (MAPK) pathway as a critical effector required for METΔex14-dependent growth. Ectopic expression MET in an isogenic cell line model showed that overexpression of the mutant METΔex14 receptor led to higher levels of MAPK phosphorylation and nuclear import, resulting in increased expression and phosphorylation of nuclear MAPK targets. In comparison, other known MET effectors were unaffected. Inhibition of this pathway by KRAS knockdown in MET-addicted cells in vitro led to decreased viability in only the METΔex14-expressing cells. Conversely, decoupling RAS-MAPK axis, but not other effector pathways, from MET activity via the introduction of constitutively active mutants conferred resistance to MET inhibitors in vitro. Our results suggest that aberrant hyperactivity of the MET receptor caused by the exon 14-skipping mutation does not uniformly upregulate all known downstream effectors, rather gaining a predilection for aberrantly activating and subsequently relying on the RAS-MAPK pathway. These findings provide a rationale for the co-targeting of the RAS-MAPK pathway alongside MET to prolong therapeutic response and circumvent resistance to improve patient survival.
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Project description:We have previously shown that some gefitinib insensitive head and neck squamous cell carcinoma (HNSCC) cell lines exhibit dominant autocrine fibroblast growth factor receptor (FGFR) signaling. Herein, we deployed a whole genome loss-of-function screen to identify genes whose knockdown potentiated the inhibitory effect of the FGFR inhibitor, AZ12908010, in HNSCC cell lines. Three HNSCC cell lines expressing a genome-wide shRNA library were treated with AZ8010 and the abundance of shRNA sequences was assessed by deep sequencing. Synthetic lethal hits were validated through use of specific inhibitors and independent shRNAs. We found that multiple alternate receptors provided protection from FGFR inhibition, including the receptor tyrosine kinases (RTKs), epidermal growth factor receptor 2 (ERBB2) and hepatocyte growth factor receptor (MET). We showed that specific knockdown of either ERBB2 or MET in combination with FGFR inhibition led to increased inhibition of growth relative to FGFR tyrosine kinase inhibitor (TKI) treatment alone. These results were confirmed using specific small molecule inhibitors of either ERBB family members or MET. Moreover, the combination of FGFR, MET and ERBB family inhibitors showed the largest inhibition of growth as compared to the double combinations. These results reveal a role for alternate RTKs in maintaining pro-growth and survival signaling in HNSCC cells in the setting of FGFR inhibition. Thus, improved therapies for HNSCC patients could involve rationally designed combinations of TKIs targeting FGFR, ERBB family members and MET.
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