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Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer.

Overview of attention for article published in Clinical Cancer Research, July 2023
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  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (94th percentile)
  • High Attention Score compared to outputs of the same age and source (93rd percentile)

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Title
Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer.
Published in
Clinical Cancer Research, July 2023
DOI 10.1158/1078-0432.ccr-22-3930
Pubmed ID
Authors

Harshabad Singh, Rachel B Keller, Kevin S Kapner, Julien Dilly, Srivatsan Raghavan, Chen Yuan, Elizabeth F Cohen, Michael Tolstorukov, Elizabeth Andrews, Lauren K Brais, Annacarolina da Silva, Kimberly Perez, Douglas A Rubinson, Rishi Surana, Marios Giannakis, Kimmie Ng, Thomas E Clancy, Matthew B Yurgelun, Benjamin L Schlechter, Jeffrey W Clark, Geoffrey I Shapiro, Michael H Rosenthal, Jason L Hornick, Valentina Nardi, Yvonne Y Li, Hersh Gupta, Andrew D Cherniack, Matthew Meyerson, James M Cleary, Jonathan A Nowak, Brian M Wolpin, Andrew J Aguirre

Abstract

Approximately 8-10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents. We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multi-gene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer. Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the mitogen activated kinase (MAPK) pathway, including BRAF mutations and in-frame deletions and receptor-tyrosine kinase (RTK) fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers such as GNAS, MYC, PIK3CA and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid (PDO) models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (Median Age: 62.6 vs. 65.7 years , p = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases. This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials.

X Demographics

X Demographics

The data shown below were collected from the profiles of 74 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 5 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 5 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 3 60%
Student > Ph. D. Student 1 20%
Student > Master 1 20%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 4 80%
Agricultural and Biological Sciences 1 20%
Medicine and Dentistry 1 20%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 39. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 05 December 2023.
All research outputs
#1,046,766
of 25,372,398 outputs
Outputs from Clinical Cancer Research
#698
of 13,206 outputs
Outputs of similar age
#19,295
of 352,437 outputs
Outputs of similar age from Clinical Cancer Research
#11
of 147 outputs
Altmetric has tracked 25,372,398 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 95th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 13,206 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 11.7. This one has done particularly well, scoring higher than 94% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 352,437 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 94% of its contemporaries.
We're also able to compare this research output to 147 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 93% of its contemporaries.