Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor-specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.

Systems Biology Ireland University College Dublin Dublin Ireland

Systems Biology Ireland University College Dublin Dublin Ireland; Conway Institute of Biomolecular and Biomedical Research University College Dublin Dublin Ireland; School of Medicine and Medical Science University College Dublin Dublin Ireland

Systems Biology Ireland University College Dublin Dublin Ireland; Conway Institute of Biomolecular and Biomedical Research University College Dublin Dublin Ireland; School of Medicine and Medical Science University College Dublin Dublin Ireland; Department of Pharmacology Yale University School of Medicine New Haven CT USA

Systems Biology Ireland University College Dublin Dublin Ireland; Department of Histology and Embryology Faculty of Medicine and Dentistry Palacky University 779 00 Olomouc Czech Republic

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Mollinedo F, and Gajate C (2019). Novel therapeutic approaches for pancreatic cancer by combined targeting of RAF→MEK→ERK signaling and autophagy survival response. Ann. Transl. Med 7, S153. 10.21037/atm.2019.06.40. PubMed DOI PMC

Hosein AN, Dougan SK, Aguirre AJ, and Maitra A (2022). Translational advances in pancreatic ductal adenocarcinoma therapy. Nat. Can. (Ott.) 3, 272–286. 10.1038/s43018-022-00349-2. PubMed DOI

Lei F, Xi X, Batra SK, and Bronich TK (2019). Combination Therapies and Drug Delivery Platforms in Combating Pancreatic Cancer. J. Pharmacol. Exp. Therapeut 370, 682–694. 10.1124/jpet.118.255786. PubMed DOI PMC

Hobbs GA, Der CJ, and Rossman KL (2016). RAS isoforms and mutations in cancer at a glance. J. Cell Sci 129, 1287–1292. 10.1242/jcs.182873. PubMed DOI PMC

Punekar SR, Velcheti V, Neel BG, and Wong K-K (2022). The current state of the art and future trends in RAS-targeted cancer therapies. Nat. Rev. Clin. Oncol 19, 637–655. 10.1038/s41571-022-00671-9. PubMed DOI PMC

Ostrem JM, Peters U, Sos ML, Wells JA, and Shokat KM (2013). K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551. 10.1038/nature12796. PubMed DOI PMC

Diehl JN, Hibshman PS, Ozkan-Dagliyan I, Goodwin CM, Howard SV, Cox AD, and Der CJ (2022). Targeting the ERK mitogen-activated protein kinase cascade for the treatment of KRAS-mutant pancreatic cancer. In RAS: Past, Present, and Future (Elsevier), pp. 101–130. 10.1016/bs.acr.2021.07.008. PubMed DOI

Cowzer D, Zameer M, Conroy M, Kolch W, and Duffy AG (2022). Targeting KRAS in Pancreatic Cancer. J. Personalized Med 12, 1870. 10.3390/jpm12111870. PubMed DOI PMC

Borazanci Erkut (2023). Phase II Trial of Vemurafenib and Sorafenib in Pancreatic Cancer. ClinicalTrials.gov ID NCT05068752. https://clinicaltrials.gov/study/NCT05068752.

Karoulia Z, Gavathiotis E, and Poulikakos PI (2017). New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer 17, 676–691. 10.1038/nrc.2017.79. PubMed DOI PMC

Sanchez-Laorden B, Viros A, Girotti MR, Pedersen M, Saturno G, Zambon A, Niculescu-Duvaz D, Turajlic S, Hayes A, Gore M, et al. (2014). BRAF Inhibitors Induce Metastasis in RAS Mutant or Inhibitor-Resistant Melanoma Cells by Reactivating MEK and ERK Signaling. Sci. Signal 7, ra30. 10.1126/scisignal.2004815. PubMed DOI

Lito P, Rosen N, and Solit DB(2013).Tumor adaptation and resistance to RAF inhibitors. Nat. Med 19, 1401–1409. 10.1038/nm.3392. PubMed DOI

Rukhlenko OS, Khorsand F, Krstic A, Rozanc J, Alexopoulos LG, Rauch N, Erickson KE, Hlavacek WS, Posner RG, Gómez-Coca S, et al. (2018). Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. Cell Syst. 7, 161–179.e14. 10.1016/j.cels.2018.06.002. PubMed DOI PMC

Agianian B, and Gavathiotis E (2018). Current Insights of BRAF Inhibitors in Cancer at American. J. Med. Chem 61, 5775–5793. 10.1021/acs.jmedchem.7b01306. PubMed DOI

Kholodenko BN (2015). Drug Resistance Resulting from Kinase Dimerization Is Rationalized by Thermodynamic Factors Describing Allosteric Inhibitor Effects. Cell Rep. 12, 1939–1949. 10.1016/j.celrep.2015.08.014. PubMed DOI

Cotto-Rios XM, Agianian B, Gitego N, Zacharioudakis E, Giricz O, Wu Y, Zou Y, Verma A, Poulikakos PI, and Gavathiotis E (2020). Inhibitors of BRAF dimers using an allosteric site. Nat. Commun 11, 4370. 10.1038/s41467-020-18123-2. PubMed DOI PMC

Kholodenko BN, Rauch N, Kolch W, and Rukhlenko OS (2021). A systematic analysis of signaling reactivation and drug resistance. Cell Rep. 35, 109157. 10.1016/j.celrep.2021.109157. PubMed DOI PMC

Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, Kovatich AJ, Benz CC, Levine DA, Lee AV, et al. (2018). An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics. Cell 173, 400–416.e11. 10.1016/j.cell.2018.02.052. PubMed DOI PMC

Schubert M, Klinger B, Klünemann M, Sieber A, Uhlitz F, Sauer S, Garnett MJ, Blüthgen N, and Saez-Rodriguez J (2018). Perturbation-response genes reveal signaling footprints in cancer gene expression. Nat. Commun 9, 20. 10.1038/s41467-017-02391-6. PubMed DOI PMC

Jia Y, Jiang T, Li X, Zhao C, Zhang L, Zhao S, Liu X, Qiao M, Luo J, Shi J, et al. (2017). Characterization of distinct types of KRAS mutation and its impact on first-line platinum-based chemotherapy in Chinese patients with advanced non-small cell lung cancer. Oncol. Lett 14, 6525–6532. 10.3892/ol.2017.7016. PubMed DOI PMC

Nusrat F, Khanna A, Jain A, Jiang W, Lavu H, Yeo CJ, Bowne W, and Nevler A (2024). The Clinical Implications of KRAS Mutations and Variant Allele Frequencies in Pancreatic Ductal Adenocarcinoma. J. Clin. Med 13, 2103. 10.3390/jcm13072103. PubMed DOI PMC

Hanrahan AJ, Chen Z, Rosen N, and Solit DB (2024). BRAF — a tumour-agnostic drug target with lineage-specific dependencies. Nat. Rev. Clin. Oncol 21, 224–247. 10.1038/s41571-023-00852-0. PubMed DOI PMC

Collisson EA, Trejo CL, Silva JM, Gu S, Korkola JE, Heiser LM, Charles R-P, Rabinovich BA, Hann B, Dankort D, et al. (2012). A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2, 685–693. 10.1158/2159-8290.CD-11-0347. PubMed DOI PMC

Hayes TK, Neel NF, Hu C, Gautam P, Chenard M, Long B, Aziz M, Kassner M, Bryant KL, Pierobon M, et al. (2016). Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression. Cancer Cell 29, 75–89. 10.1016/j.ccell.2015.11.011. PubMed DOI PMC

Long J, Zhang Y, Yu X, Yang J, LeBrun DG, Chen C, Yao Q, and Li M (2011). Overcoming drug resistance in pancreatic cancer. Expert Opin. Ther. Targets 15, 817–828. 10.1517/14728222.2011.566216. PubMed DOI PMC

Brown WS, McDonald PC, Nemirovsky O, Awrey S, Chafe SC, Schaeffer DF, Li J, Renouf DJ, Stanger BZ, and Dedhar S (2020). Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer. Cell Rep. Med 1, 100131. 10.1016/j.xcrm.2020.100131. PubMed DOI PMC

Gurreri E, Genovese G, Perelli L, Agostini A, Piro G, Carbone C, and Tortora G (2023). KRAS-Dependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy. Int. J. Mol. Sci 24, 9313. 10.3390/ijms24119313. PubMed DOI PMC

Wong MH, Xue A, Baxter RC, Pavlakis N, and Smith RC (2016). Upstream and Downstream Co-inhibition of Mitogen-Activated Protein Kinase and PI3K/Akt/mTOR Pathways in Pancreatic Ductal Adenocarcinoma. Neoplasia 18, 425–435. 10.1016/j.neo.2016.06.001. PubMed DOI PMC

Soares HP, Ming M, Mellon M, Young SH, Han L, Sinnet-Smith J, and Rozengurt E (2015). Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2. Mol. Cancer Therapeut 14, 1014–1023. 10.1158/1535-7163.MCT-14-0669. PubMed DOI PMC

Meyers N, Gérard C, Lemaigre FP, and Jacquemin P (2020). Differential impact of the ERBB receptors EGFR and ERBB2 on the initiation of precursor lesions of pancreatic ductal adenocarcinoma. Sci. Rep 10, 5241. 10.1038/s41598-020-62106-8. PubMed DOI PMC

Lu H, Liu S, Zhang G, Wu B, Zhu Y, Frederick DT, Hu Y, Zhong W, Randell S, Sadek N, et al. (2017). PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. Nature 550, 133–136. 10.1038/nature24040. PubMed DOI PMC

Manole S, Richards EJ, and Meyer AS (2016). JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2–Targeted Therapies. Cancer Res. 76, 5219–5228. 10.1158/0008-5472.CAN-16-0123. PubMed DOI PMC

Lipner MB, Peng XL, Jin C, Xu Y, Gao Y, East MP, Rashid NU, Moffitt RA, Herrera Loeza SG, Morrison AB, et al. (2020). Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy. JCI Insight 5, e129905. 10.1172/jci.insight.129905. PubMed DOI PMC

Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, Sanderson MP, Kessler D, Trapani F, Arnhof H, et al. (2021). BI-3406, a Potent and Selective SOS1–KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition. Cancer Discov. 11, 142–157. 10.1158/2159-8290.CD-20-0142. PubMed DOI PMC

Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, Schuman SS, Shea JE, Seipp MT, Yap JT, et al. (2019). Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat. Med 25, 620–627. 10.1038/s41591-019-0367-9. PubMed DOI PMC

Huang C, Du R, Jia X, Liu K, Qiao Y, Wu Q, Yao N, Yang L, Zhou L, Liu X, et al. (2022). CDK15 promotes colorectal cancer progression via phosphorylating PAK4 and regulating β-catenin/MEK-ERK signaling pathway. Cell Death Differ. 29, 14–27. 10.1038/s41418-021-00828-6. PubMed DOI PMC

Wu CF, Liu S, Lee Y-C, Wang R, Sun S, Yin F, Bornmann WG, Yu-Lee L-Y, Gallick GE, Zhang W, et al. (2014). RSK promotes G2/M transition through activating phosphorylation of Cdc25A and Cdc25B. Oncogene 33, 2385–2394. 10.1038/onc.2013.182. PubMed DOI PMC

Mitra A, Ross JA, Rodriguez G, Nagy ZS, Wilson HL, and Kirken RA (2012). Signal Transducer and Activator of Transcription 5b (Stat5b) Serine 193 Is a Novel Cytokine-induced Phospho-regulatory Site That Is Constitutively Activated in Primary Hematopoietic Malignancies. J. Biol. Chem 287, 16596–16608. 10.1074/jbc.M111.319756. PubMed DOI PMC

Demarchi F, Bertoli C, Sandy P, and Schneider C (2003). Glycogen Synthase Kinase-3β Regulates NF-κB1/p105 Stability. J. Biol. Chem 278, 39583–39590. 10.1074/jbc.M305676200. PubMed DOI

Silke J, and O’Reilly LA (2021). NF-κB and Pancreatic Cancer; Chapter and Verse. Cancers 13, 4510. 10.3390/cancers13184510. PubMed DOI PMC

Armaiz-Pena GN, Allen JK, Cruz A, Stone RL, Nick AM, Lin YG, Han LY, Mangala LS, Villares GJ, Vivas-Mejia P, et al. (2013). Src activation by β-adrenoreceptors is a key switch for tumour metastasis. Nat. Commun 4, 1403. 10.1038/ncomms2413. PubMed DOI PMC

Jha RK, Kouzine F, and Levens D (2023). MYC function and regulation in physiological perspective. Front. Cell Dev. Biol 11, 1268275. 10.3389/fcell.2023.1268275. PubMed DOI PMC

Adachi Y, Kimura R, Hirade K, and Ebi H (2021). Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers. Cancers 13, 5081. 10.3390/cancers13205081. PubMed DOI PMC

Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, and Settleman J (2009). A Gene Expression Signature Associated with “K-Ras Addiction” Reveals Regulators of EMT and Tumor Cell Survival. CancerCell 15, 489–500. 10.1016/j.ccr.2009.03.022. PubMed DOI PMC

Zeisberg M, and Neilson EG (2009). Biomarkers for epithelial-mesenchymal transitions. J. Clin. Invest 119, 1429–1437. 10.1172/jci36183. PubMed DOI PMC

Scanlon CS, Van Tubergen EA, Inglehart RC, D’Silva NJ, and D’Silva NJ (2013). Biomarkers of Epithelial-Mesenchymal Transition in Squamous Cell Carcinoma. J. Dent. Res 92, 114–121. 10.1177/0022034512467352. PubMed DOI PMC

Dijk F, Veenstra VL, Soer EC, Dings, Zhao L, Halfwerk JB, Hooijer GK, Damhofer H, Marzano M, Steins A, et al. (2020). Unsupervised class discovery in pancreatic ductal adenocarcinoma reveals cell-intrinsic mesenchymal features and high concordance between existing classification systems. Sci. Rep 10, 337. 10.1038/s41598-019-56826-9. PubMed DOI PMC

Espiau-Romera P, Courtois S, Parejo-Alonso B, and Sancho P (2020). Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification. J. Clin. Med 9, 4128. 10.3390/jcm9124128. PubMed DOI PMC

Tyc KM, Kazi A, Ranjan A, Wang R, and Sebti SM (2023). Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers. iScience 26, 106082. 10.1016/j.isci.2023.106082. PubMed DOI PMC

Hobbs GA, Baker NM, Miermont AM, Thurman RD, Pierobon M, Tran TH, Anderson AO, Waters AM, Diehl JN, Papke B, et al. (2020). Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer. Cancer Discov. 10, 104–123. 10.1158/2159-8290.cd-19-1006. PubMed DOI PMC

Gulay KCM, Zhang X, Pantazopoulou V, Patel J, Esparza E, Pran Babu DS, Ogawa S, Weitz J, Ng I, Mose ES, et al. (2023). Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma. Cancer Res. 83, 3001–3012. 10.1158/0008-5472.CAN-23-1313. PubMed DOI PMC

Dilly J, Hoffman MT, Abbassi L, Li Z, Paradiso F, Parent BD, Hennessey CJ, Jordan AC, Morgado M, Dasgupta S, et al. (2024). Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer. Cancer Discov. 10.1158/2159-8290.CD-24-0177. PubMed DOI PMC

Gerosa L, Chidley C, Fröhlich F, Sanchez G, Lim SK, Muhlich J, Chen JY, Vallabhaneni S, Baker GJ, Schapiro D, et al. (2020). Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells. Cell Syst. 11, 478–494.e9. 10.1016/j.cels.2020.10.002. PubMed DOI PMC

Rushworth LK, Hindley AD, O’Neill E, and Kolch W (2006). Regulation and Role of Raf-1/B-Raf Heterodimerization. Mol. Cell Biol 26, 2262–2272. 10.1128/MCB.26.6.2262-2272.2006. PubMed DOI PMC

Karoulia Z, Wu Y, Ahmed TA, Xin Q, Bollard J, Krepler C, Wu X, Zhang C, Bollag G, Herlyn M, et al. (2016). An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. Cancer Cell 30, 485–498. 10.1016/j.ccell.2016.06.024. PubMed DOI PMC

Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM, Chang MT, Drosten M, Zhao H, Cecchi F, Hembrough T, et al. (2017). Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 548, 234–238. 10.1038/nature23291. PubMed DOI PMC

Dorel M, Klinger B, Gross T, Sieber A, Prahallad A, Bosdriesz E, Wessels LFA, and Blüthgen N (2018). Modelling signalling networks from perturbation data. Bioinformatics 34, 4079–4086. 10.1093/bioinformatics/bty473. PubMed DOI

Klinger B, Sieber A, Fritsche-Guenther R, Witzel F, Berry L, Schumacher D, Yan Y, Durek P, Merchant M, Schäfer R, et al. (2013). Network quantification of EGFR signaling unveils potential for targeted combination therapy. Mol. Syst. Biol 9, 673. 10.1038/msb.2013.29. PubMed DOI PMC

Berlak M, Tucker E, Dorel M, Winkler A, McGearey A, Rodriguez-Fos E, da Costa BM, Barker K, Fyle E, Calton E, et al. (2022). Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells. Mol. Cancer 21, 126. 10.1186/s12943-022-01583-z. PubMed DOI PMC

Kiyatkin A, Aksamitiene E, Markevich NI, Borisov NM, Hoek JB, and Kholodenko BN (2006). Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops. J. Biol. Chem 281, 19925–19938. 10.1074/jbc.m600482200. PubMed DOI PMC

Erickson KE, Rukhlenko OS, Posner RG, Hlavacek WS, and Kholodenko BN (2019). New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling. Semin. Cancer Biol 54, 162–173. 10.1016/j.semcancer.2018.02.008. PubMed DOI PMC

Kholodenko BN, Kiyatkin A, Bruggeman FJ, Sontag E, Westerhoff HV, and Hoek JB (2002). Untangling the wires: A strategy to trace functional interactions in signaling and gene networks. Proc. Natl. Acad. Sci. USA 99, 12841–12846. 10.1073/pnas.192442699. PubMed DOI PMC

Adamopoulos C, Ahmed TA, Tucker MR, Ung PMU, Xiao M, Karoulia Z, Amabile A, Wu X, Aaronson SA, Ang C, et al. (2021). Exploiting Allosteric Properties of RAF and MEK Inhibitors to Target Therapy-Resistant Tumors Driven by Oncogenic BRAF Signaling. Cancer Discov. 11, 1716–1735. 10.1158/2159-8290.cd-20-1351. PubMed DOI PMC

Wilhelm SM, Carter C, Tang L, Wilkie D, Mcnabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, et al. (2004). BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis. Cancer Res. 64, 7099–7109. 10.1158/0008-5472.can-04-1443. PubMed DOI

Vin H, Ojeda SS, Ching G, Leung ML, Chitsazzadeh V, Dwyer DW, Adelmann CH, Restrepo M, Richards KN, Stewart LR, et al. (2013). BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling. Elife 2, e00969. 10.7554/elife.00969. PubMed DOI PMC

Adelmann CH, Ching G, Du L, Saporito RC, Bansal V, Pence LJ, Liang R, Lee W, and Tsai KY (2016). Comparative profiles of BRAF inhibitors: the paradox index as a predictor of clinical toxicity. Oncotarget 7, 30453–30460. 10.18632/oncotarget.8351. PubMed DOI PMC

Okaniwa M, Hirose M, Arita T, Yabuki M, Nakamura A, Takagi T, Kawamoto T, Uchiyama N, Sumita A, Tsutsumi S, et al. (2013). Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of C-7-Substituted 1,3-Benzothiazole Derivatives. J. Med. Chem 56, 6478–6494. 10.1021/jm400778d. PubMed DOI

Brooks EA, Galarza S, Gencoglu MF, Cornelison RC, Munson JM, Peyton SR, Cornelison RC, Munson JM, and Peyton SR (2019). Applicability of drug response metrics for cancer studies using biomaterials. Philos. Trans. R. Soc. Lond. B Biol. Sci 374, 20180226. 10.1098/rstb.2018.0226. PubMed DOI PMC

Turner RJ, and Charlton SJ (2005). Assessing the Minimum Number of Data Points Required for Accurate IC50 Determination. Assay Drug Dev. Technol 3, 525–531. 10.1089/adt.2005.3.525. PubMed DOI

Kelstrup CD, Bekker-Jensen DB, Arrey TN, Hogrebe A, Harder A, and Olsen JV (2018). Performance Evaluation of the Q Exactive HF-X for Shotgun Proteomics. J. Proteome Res 17, 727–738. 10.1021/acs.jproteome.7b00602. PubMed DOI

Meier F, Beck S, Grassl N, Lubeck M, Park MA, Raether O, and Mann M (2015). Parallel Accumulation–Serial Fragmentation (PASEF): Multiplying Sequencing Speed and Sensitivity by Synchronized Scans in a Trapped Ion Mobility Device. J. Proteome Res 14, 5378–5387. 10.1021/acs.jproteome.5b00932. PubMed DOI

Yu F, Teo GC, Kong AT, Fröhlich K, Li GX, Demichev V, and Nesvizhskii AI (2023). Analysis of DIA proteomics data using MSFragger-DIA and FragPipe computational platform. Nat. Commun 14, 4154. 10.1038/s41467-023-39869-5. PubMed DOI PMC

Demichev V, Messner CB, Vernardis SI, Lilley KS, and Ralser M (2020). DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat. Methods 17, 41–44. 10.1038/s41592-019-0638-x. PubMed DOI PMC

Imoto H, Rauch N, Neve AJ, Khorsand F, Kreileder M, Alexopoulos LG, Rauch J, Okada M, Kholodenko BN, and Rukhlenko OS (2023). A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression. Biomolecules 13, 1212. 10.3390/biom13081212. PubMed DOI PMC

Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, Gill S, Harrington WF, Pantel S, Krill-Burger JM, et al. (2017). Defining a Cancer Dependency Map. Cell 170, 564–576.e16. 10.1016/j.cell.2017.06.010. PubMed DOI PMC

Therneau T. (2023). A Package for Survival Analysis in R; Version 3.2-11. 10.32614/CRAN.package.survival. DOI

Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, Benfeitas R, Arif M, Liu Z, Edfors F, et al. (2017). A pathology atlas of the human cancer transcriptome. Science 357, eaan2507. 10.1126/science.aan2507. PubMed DOI

Lopez CF, Muhlich JL, Bachman JA, and Sorger PK (2013). Programming biological models in Python using PySB. Mol. Syst. Biol 9, 646. 10.1038/msb.2013.1. PubMed DOI PMC

Harris LA, Hogg JS, Tapia JJ, Sekar JAP, Gupta S, Korsunsky I, Arora A, Barua D, Sheehan RP, and Faeder JR (2016). BioNetGen 2.2: advances in rule-based modeling. Bioinformatics 32, 3366–3368. 10.1093/bioinformatics/btw469. PubMed DOI PMC

Fröhlich F, Gerosa L, Muhlich J, and Sorger PK (2023). Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance. Mol. Syst. Biol 19, e10988. 10.15252/msb.202210988. PubMed DOI PMC

Sekar JAP, Hogg JS, and Faeder JR (2016). Energy-based modeling in BioNetGen. In 2016 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) (IEEE). 10.1109/bibm.2016.7822739. DOI

Kawasaki Y, Sakimura A, Park CM, Tomaru R, Tanaka T, Ozawa T, Zhou Y, Narita K, Kishi H, Muraguchi A, and Sakurai H (2016). Feedback control of ErbB2 via ERK-mediated phosphorylation of a conserved threonine in the juxtamembrane domain. Sci. Rep 6, 31502. 10.1038/srep31502. PubMed DOI PMC

Lake D, Corrêa SAL, and Müller J, (2016). Negative feedback regulation of the ERK1/2 MAPK pathway. Cell. Mol. Life Sci 73, 4397–4413. 10.1007/s00018-016-2297-8. PubMed DOI PMC

Lavoie H, Gagnon J, and Therrien M (2020). ERK signalling: a master regulator of cell behaviour, life and fate. Nat. Rev. Mol. Cell Biol 21, 607–632. 10.1038/s41580-020-0255-7. PubMed DOI

Kholodenko BN, Demin OV, Moehren G, and Hoek JB (1999). Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor. J. Biol. Chem 274, 30169–30181. 10.1074/jbc.274.42.30169. PubMed DOI

Saha M, Carriere A, Cheerathodi M, Zhang X, Lavoie G, Rush J, Roux PP, and Ballif BA (2012). RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation. Biochem. J 447, 159–166. 10.1042/BJ20120938. PubMed DOI PMC

Borisov N, Aksamitiene E, Kiyatkin A, Legewie S, Berkhout J, Maiwald T, Kaimachnikov NP, Timmer J, Hoek JB, and Kholodenko BN (2009). Systems-level interactions between insulin-EGF networks amplify mitogenic signaling. Mol. Syst. Biol 5, 256. 10.1038/msb.2009.19. PubMed DOI PMC

Yoneyama Y, Inamitsu T, Chida K, Iemura S-I, Natsume T, Maeda T, Hakuno F, and Takahashi S-I (2018). Serine Phosphorylation by mTORC1 Promotes IRS-1 Degradation through SCFβ-TRCP E3 Ubiquitin Ligase. iScience 5, 1–18. 10.1016/j.isci.2018.06.006. PubMed DOI PMC

McFall T, and Stites EC (2021). Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach. Cell Rep. 37, 110096. 10.1016/j.celrep.2021.110096. PubMed DOI PMC

Hu J, Stites EC, Yu H, Germino EA, Meharena HS, Stork PJS, Kornev AP, Taylor SS, and Shaw AS (2013). Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers. Cell 154, 1036–1046. 10.1016/j.cell.2013.07.046. PubMed DOI PMC

Lavoie H, and Therrien M (2015). Regulation of RAF protein kinases in ERK signalling. Nat. Rev. Mol. Cell Biol 16, 281–298. 10.1038/nrm3979. PubMed DOI

Chou TC (2010). Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method. Cancer Res. 70, 440–446. 10.1158/0008-5472.can-09-1947. PubMed DOI

Chou TC (2008). Preclinical versus clinical drug combination studies. Leuk. Lymphoma 49, 2059–2080. 10.1080/10428190802353591. PubMed DOI

Ianevski A, Giri AK, and Aittokallio T (2020). SynergyFinder 2.0: visual analytics of multi-drug combination synergies. Nucleic Acids Res. 48, W488–W493. 10.1093/nar/gkaa216. PubMed DOI PMC