Functional measurement of mitogen-activated protein kinase pathway activation predicts responsiveness of RAS-mutant cancers to MEK inhibitors

Kato, Shumei; Porter, Robert; Okamura, Ryosuke; Lee, Suzanna; Zelichov, Ori; Tarcic, Gabi; Vidne, Michael; Kurzrock, Razelle

doi:10.1016/j.ejca.2021.01.055

Cited by 4 publications

(3 citation statements)

References 24 publications

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“…These observations support our prior reports that combinations of targeted agents, such as matched CDK4/6 inhibitors and MEK inhibitors (given when cognate pathway co-alterations such CDKN2A/B loss and KRAS mutations are may have activity, even when single agents are ineffective 43 . The current results also reflect the need for implementation of multi-omic and functional testing for all patients with advanced pancreatic cancer, perhaps earlier in the course of the disease, to further identify actionable alterations 26,44 . Prospective trials of this strategy are warranted.…”

Section: Discussionmentioning

confidence: 56%

Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis

Shaya¹,

Kato²,

Adashek³

et al. 2023

npj Genom. Med.

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Despite progress, 2-year pancreatic cancer survival remains dismal. We evaluated a biomarker-driven, combination/N-of-one strategy in 18 patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor Board). Targeted agents administered/patient = 2.5 (median) (range, 1–4); first-line therapy (N = 5); second line, (N = 13). Comparing patients (high versus low degrees of matching) (matching score ≥50% versus <50%; reflecting number of alterations matched to targeted agents divided by number of pathogenic alterations), survival was significantly longer (hazard ratio [HR] 0.24 (95% confidence interval [CI], 0.078–0.76, P = 0.016); clinical benefit rates (CBR) (stable disease ≥6 months/partial/complete response) trended higher (45.5 vs 0.0%, P = 0.10); progression-free survival, HR, 95% CI, 0.36 (0.12–1.10) (p = 0.075). First versus ≥2nd-line therapy had higher CBRs (80.0 vs 7.7%, P = 0.008). No grade 3–4 toxicities occurred. The longest responder achieved partial remission (17.5 months) by co-targeting MEK and CDK4/6 alterations (chemotherapy-free). Therefore, genomically matched targeted agent combinations were active in these advanced pancreatic cancers. Larger prospective trials are warranted.

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Section: Discussionmentioning

confidence: 56%

Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis

Shaya¹,

Kato²,

Adashek³

et al. 2023

npj Genom. Med.

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“…Moreover, targeted agents that inhibit protein expression/activity of proteins and pathways identified in our signaling defined clusters ( Figure 5 A), as well as those associated with poor DRFS, could be prioritized and considered in next iterations of clinical trials such as I-SPY 2.2. Many of the proteins/phosphoproteins that we found to be significantly expressed/activated as markers of global resistance, non-pCR, and/or poor DRFS correlate with cell culture-based drug sensitivity 43 , 44 as well as clinical response 13 , 23 , 40 , 45 , 46 , 47 to drugs that target those specific proteins (HER2, EGFR, TIE2, AR, AKT, mTOR, etc.). These data support the functional significance of our findings and provide justification for further exploration of the implied therapeutic strategies in prospective trials.…”

Section: Discussionmentioning

confidence: 82%

“… 39 Our findings that increased cyclin D1 appears to be a universal resistance marker across all HR/HER2 subtypes suggest that cyclin D1 could be an actionable target using therapeutic approaches that promote tumor senescence or by modulating the cell cycle directly using CDK4/6 inhibitors (in the case of HER2+ tumors). 40 …”

Section: Discussionmentioning

confidence: 99%

Protein signaling and drug target activation signatures to guide therapy prioritization: Therapeutic resistance and sensitivity in the I-SPY 2 Trial

Gallagher,

Wulfkuhle,

Wolf

et al. 2023

Cell Reports Medicine

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Therapeutic Targeting of RAS Mutant Cancers

Stites

Paskvan²,

Kato³

2022

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The KRAS oncogene is believed to be the most common single nucleotide variant oncogene in human cancer. Historically, efforts to target KRAS and the other RAS GTPases have struggled. More recently, efforts have focused on identifying and exploiting features unique to specific oncogenic mutations. This has led to the first FDA approval for a RAS targeted therapy. This new agent is a covalent inhibitor that reacts with the cysteine residue created by a codon 12 glycine to cysteine (G12C) mutation within KRAS. Mutant-specific strategies may also exist for other KRAS single nucleotide variants, and recent studies provide examples and mechanisms.

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Functional measurement of mitogen-activated protein kinase pathway activation predicts responsiveness of RAS-mutant cancers to MEK inhibitors

Cited by 4 publications

References 24 publications

Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis

Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis

Protein signaling and drug target activation signatures to guide therapy prioritization: Therapeutic resistance and sensitivity in the I-SPY 2 Trial

Therapeutic Targeting of RAS Mutant Cancers

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