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Although distinct biochemical properties have been described for individual KRAS mutants, whether they generate unique allele-specific signalling programmes in PDAC cells remains unresolved. Here, we systematically interrogated the molecular consequences of seven common KRAS mutant variants in reconstituted isogenic, KRAS-deficient PDAC cell lines by integrated transcriptomic, proteomic, and phosphoproteomic profiling. We found that baseline cellular state, rather than allele identity, was the predominant driver of molecular variation. Comparisons with established KRAS reference signatures revealed significant but moderate overlap at the mRNA level and less so at the proteome level. Pathway analyses highlighted the interferon response and mitochondrial translation-related proteins as recurrently altered across mutant alleles, while phosphoproteomic data confirmed robust extracellular signal-regulated kinase 1\/2 (ERK1\/2) activity and the suppression of dual-specificity tyrosine phosphorylation-regulated kinase substrates by mutant KRAS expression. Importantly, no robust mutant allele-specific molecular programmes were identified in our KRAS-reconstituted cell lines. Together, our study establishes a comprehensive multi-omics resource for KRAS signalling in PDAC and demonstrates that cellular context exerts a stronger influence than allele identity in shaping molecular profiles, with implications for interpreting putative allele-specific signalling dependencies.<\/jats:p>","DOI":"10.1093\/molecular-omics\/aaiag022","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:43:31Z","timestamp":1789044211000},"source":"Crossref","is-referenced-by-count":0,"title":["Baseline cellular state shapes the molecular impact of mutant\n                    <i>Kirsten rat sarcoma viral oncogene homologue<\/i>\n                    (\n                    <i>KRAS<\/i>\n                    ) alleles in reconstituted pancreatic cancer cells"],"prefix":"10.1093","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2238-766X","authenticated-orcid":false,"given":"Yanixa","family":"Qui\u00f1ones-Avil\u00e9s","sequence":"first","affiliation":[{"name":"Yale Cancer Biology Institute, Yale University , West Haven, CT 06516 ,","place":["United States"]},{"name":"Department of Genetics, Yale University School of Medicine , New Haven, CT 06520 ,","place":["United States"]},{"name":"Combined Program in the Biological and Biomedical Sciences , Graduate School of Arts and Sciences, Yale University, New Haven, CT 06520 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Salovska","sequence":"additional","affiliation":[{"name":"Yale Cancer Biology Institute, Yale University , West Haven, CT 06516 ,","place":["United States"]},{"name":"Department of Pharmacology, Yale University School of Medicine , New Haven, CT 06520 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra S","family":"Markham","sequence":"additional","affiliation":[{"name":"Yale Cancer Biology Institute, Yale University , West Haven, CT 06516 ,","place":["United States"]},{"name":"Department of Genetics, Yale University School of Medicine , New Haven, CT 06520 ,","place":["United States"]},{"name":"Combined Program in the Biological and Biomedical Sciences , Graduate School of Arts and Sciences, Yale University, New Haven, CT 06520 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Di","sequence":"additional","affiliation":[{"name":"Yale Cancer Biology Institute, Yale University , West Haven, CT 06516 ,","place":["United States"]},{"name":"Department of Pharmacology, Yale University School of Medicine , New Haven, CT 06520 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin E","family":"Turk","sequence":"additional","affiliation":[{"name":"Combined Program in the Biological and Biomedical Sciences, Graduate School of Arts and Sciences, Yale University , New Haven, CT 06520 ,","place":["United States"]},{"name":"Department of Pharmacology, Yale University School of Medicine , New Haven, CT 06520 ,","place":["United States"]},{"name":"Yale Cancer Center , Yale University School of Medicine, New Haven, CT 06510 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2626-3912","authenticated-orcid":false,"given":"Yansheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Yale Cancer Biology Institute, Yale University , West Haven, CT 06516 ,","place":["United States"]},{"name":"Combined Program in the Biological and Biomedical Sciences, Graduate School of Arts and Sciences, Yale University , New Haven, CT 06520 ,","place":["United States"]},{"name":"Department of Pharmacology, Yale University School of Medicine , New Haven, CT 06520 ,","place":["United States"]},{"name":"Yale Cancer Center , Yale University School of Medicine, New Haven, CT 06510 ,","place":["United States"]},{"name":"Department of Biomedical Informatics & Data Science, Yale University School of Medicine , New Haven, CT 06510 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7424-7223","authenticated-orcid":false,"given":"Mandar Deepak","family":"Muzumdar","sequence":"additional","affiliation":[{"name":"Yale Cancer Biology Institute, Yale University , West Haven, CT 06516 ,","place":["United States"]},{"name":"Department of Genetics, Yale University School of Medicine , New Haven, CT 06520 ,","place":["United States"]},{"name":"Combined Program in the Biological and Biomedical Sciences, Graduate School of Arts and Sciences, Yale University , New Haven, CT 06520 ,","place":["United States"]},{"name":"Yale Cancer Center , Yale University School of Medicine, New Haven, CT 06510 ,","place":["United States"]},{"name":"Department of Internal Medicine, Section of Medical Oncology and Hematology, Yale University School of Medicine , New Haven, CT 06510 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"2026092808254599300_ref1","doi-asserted-by":"publisher","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res"},{"key":"2026092808254599300_ref2","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1038\/s41591-024-03362-3","article-title":"Clinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall 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