Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (30045908)
Authors Fedele C, Ran H, Diskin B, Wei W, Jen J, Geer MJ, Araki K, Ozerdem U, Simeone DM, Miller G, Neel BG, Tang KH
Title SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models.
Journal Cancer discovery
Vol 8
Issue 10
Date 2018 Oct
URL
Abstract Text Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitroPTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancers and in wild-type RAS-expressing triple-negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEKi, and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEKi combinations could have therapeutic utility in multiple malignancies.Significance: MEK inhibitors show limited efficacy as single agents, in part because of the rapid development of adaptive resistance. We find that SHP2/MEK inhibitor combinations prevent adaptive resistance in multiple cancer models expressing mutant and wild-type KRAS. Cancer Discov; 8(10); 1237-49. ©2018 AACR.See related commentary by Torres-Ayuso and Brognard, p. 1210This article is highlighted in the In This Issue feature, p. 1195.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PTPN11 P491Q missense unknown PTPN11 P491Q lies within the tyrosine-protein phosphatase domain of the Ptpn11 protein (UniProt.org). P491Q has been demonstrated to confer resistance to SHP2 inhibitors in culture (PMID: 30045908), but has not been biochemically characterized and therefore, its effect on Ptpn11 protein function is unknown (PubMed, May 2020). Y
PTPN11 Q257L missense unknown PTPN11 Q257L lies within the tyrosine-protein phosphatase domain of the Ptpn11 protein (UniProt.org). Q257L has been demonstrated to confer resistance to SHP2 inhibitors in combination with T253M in culture (PMID: 30045908), but has not been biochemically characterized and therefore, its effect on Ptpn11 protein function is unknown (PubMed, Jul 2020).
PTPN11 T253M missense unknown PTPN11 T253M lies within the tyrosine-protein phosphatase domain of the Ptpn11 protein (UniProt.org). T253M has been demonstrated to confer resistance to SHP2 inhibitors in combination with Q257L in culture (PMID: 30045908), but has not been biochemically characterized and therefore, its effect on Ptpn11 protein function is unknown (PubMed, Jul 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown pancreatic ductal adenocarcinoma not applicable Selumetinib + SHP099 Preclinical - Pdx & cell culture Actionable In a preclinical study, the combination of SHP099 and Selumetinib (AZD6244) resulted in greater sensitivity compared to either agent alone in pancreatic ductal adenocarcinoma cells, demonstrating decreased cell viability and reduced colony formation in culture and decreased tumor growth in patient-derived xenograft (PDX) models (PMID: 30045908). 30045908
PTPN11 T253M PTPN11 Q257L lung non-small cell carcinoma resistant Selumetinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, pancreatic ductal adenocarcinoma cells co-expressing PTPN11 T253M and PTPN11 Q257L were resistant to the combination therapy, Selumetinib (AZD6244) and SHP099, in culture (PMID: 30045908). 30045908
Unknown unknown triple-receptor negative breast cancer not applicable Selumetinib + SHP099 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination therapy of SHP099 and Selumetinib (AZD6244) led to decreased cell viability and reduced colony formation in triple-receptor negative breast cancer cells in culture and tumor regression in xenograft models (PMID: 30045908). 30045908
Unknown unknown ovarian cancer not applicable Selumetinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, the combination therapy of Selumetinib (AZD6244) and SHP099 resulted in decreased colony formation and reduced cell viability in ovarian cancer cells in culture and inhibition of tumor growth and reduced tumor angiogenesis in a patient-derived xenograft (PDX) model of ovarian cancer (PMID: 30045908). 30045908