The Center for Cancer Systems Pharmacology

Research

Therapeutic Resistance & Sensitivity

LSP researchers aim to understand how and why tumors develop therapeutic resistance to improve strategies for treating cancer.

Kinase inhibitors remain the largest class of drugs used to treat cancer and have revolutionized treatment by targeting specific genetic mutations in tumors. Notable examples like imatinib (used in chronic myeloid leukemia), vemurafenib (used in BRAF-mutant melanoma), and CDK4/6 inhibitors (used in hormone receptor positive breast cancer) have provided enormous benefits, extending the lives of many patients. 

However, these treatments often lose their effectiveness over time as cancer cells develop resistance to the therapy. Resistance can be long-term and short-term, driven by permanent genetic changes or temporary adaptations to cell signaling pathways. We study resistance using systems pharmacology methods and various models (cell lines, animal models, and human tissues). Our goals are to 1) uncover ways to prevent or overcome resistance, 2) improve the durability of cancer therapies, and 3) contribute to effective treatment options that use newly developed drugs or promising combination therapies. Clinical trials informed by this research are already underway. any associated Research Centers and a list of selected publications.

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Featured Publications

Sequential apoptotic and multiplexed proteomic evaluation of single cancer cells

Lecky et al.
Science Advances. 2023 Jun 23;9(25): eadg4128. PMID: 37352344
Journal
PubMed

Receptor-driven ERK pulses reconfigure MAPK signaling and enable persistence of drug-adapted BRAF-mutant melanoma cells

Gerosa et al.
Cell Syst. 2020 Nov 18. PMCID: PMC8009031
Journal
PubMed

Related Publications

MacDonald, J. A., Bradshaw, G. A., Jochems, F., Bernards, R., & Letai, A. (2025). Apoptotic priming in senescence predicts specific senolysis by quantitative analysis of mitochondrial dependencies. Cell Death and Differentiation. https://doi.org/10.1038/s41418-024-01431-1
Girnius, N., Henstridge, A. Z., Marks, B., Yu, J. K., Gray, G. K., Sander, C., Zervantonakis, I. K., & Luna, A. (2024). Cilengitide sensitivity is predicted by overall integrin expression in breast cancer. Breast Cancer Research: BCR, 26(1), 187. https://doi.org/10.1186/s13058-024-01942-2
Letai, A., & de The, H. (2024). Conventional chemotherapy: millions of cures, unresolved therapeutic index. Nature Reviews. Cancer. https://doi.org/10.1038/s41568-024-00778-4
Loi, P., Schade, A. E., Rodriguez, C. L., Krishnan, A., Perurena, N., Nguyen, V. T. M., Xu, Y., Watanabe, M., Davis, R. A., Gardner, A., Pilla, N. F., Mattioli, K., Popow, O., Gunduz, N., Lannagan, T. R. M., Fitzgerald, S., Sicinska, E. T., Lin, J.-R., Tan, W., … Cichowski, K. (2024). Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers. Cancer Discovery, 14(12), 2430–2449. https://doi.org/10.1158/2159-8290.CD-23-0866
Schade, A. E., Perurena, N., Yang, Y., Rodriguez, C. L., Krishnan, A., Gardner, A., Loi, P., Xu, Y., Nguyen, V. T. M., Mastellone, G. M., Pilla, N. F., Watanabe, M., Ota, K., Davis, R. A., Mattioli, K., Xiang, D., Zoeller, J. J., Lin, J.-R., Morganti, S., … Cichowski, K. (2024). AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution. Nature, 635(8039), 755–763. https://doi.org/10.1038/s41586-024-08031-6
Ji, W., Du, G., Jiang, J., Lu, W., Mills, C. E., Yuan, L., Jiang, F., He, Z., Bradshaw, G. A., Chung, M., Jiang, Z., Byun, W. S., Hinshaw, S. M., Zhang, T., & Gray, N. S. (2024). Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7). European Journal of Medicinal Chemistry, 276, 116613. https://doi.org/10.1016/j.ejmech.2024.116613
Olesinski, E. A., Bhatia, K. S., Wang, C., Pioso, M. S., Lin, X. X., Mamdouh, A. M., Ng, S. X., Sandhu, V., Jasdanwala, S. S., Yilma, B., Bohl, S., Ryan, J. A., Malani, D., Luskin, M. R., Kallioniemi, O., Porkka, K., Adamia, S., Chng, W. J., Osato, M., … Bhatt, S. (2024). Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts. Blood Cancer Discovery, 5(3), 180–201. https://doi.org/10.1158/2643-3230.BCD-24-0001
Chidley, C., Darnell, A. M., Gaudio, B. L., Lien, E. C., Barbeau, A. M., Vander Heiden, M. G., & Sorger, P. K. (2024). A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments. Nature Cell Biology, 26(5), 825–838. https://doi.org/10.1038/s41556-024-01402-1
Ricciuti, B., Lamberti, G., Puchala, S. R., Mahadevan, N. R., Lin, J.-R., Alessi, J. V., Chowdhury, A., Li, Y. Y., Wang, X., Spurr, L., Pecci, F., Di Federico, A., Venkatraman, D., Barrichello, A. P., Gandhi, M., Vaz, V. R., Pangilinan, A. J., Haradon, D., Lee, E., … Awad, M. M. (2024). Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non-Small-Cell Lung Cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 42(11), 1311–1321. https://doi.org/10.1200/JCO.23.00580
Bhola, P. D., & Letai, A. (2024). The Siren Song of Synergy. Blood Cancer Discovery, OF1–OF2. https://doi.org/10.1158/2643-3230.BCD-24-0004
Zhang, X., Pant, S. M., Ritch, C. C., Tang, H.-Y., Shao, H., Dweep, H., Gong, Y.-Y., Brooks, R., Brafford, P., Wolpaw, A. J., Lee, Y., Weeraratna, A., Sehgal, A., Herlyn, M., Kossenkov, A., Speicher, D., Sorger, P. K., Santagata, S., & Dang, C. V. (2024). Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity. Nature Communications, 15(1), 633. https://doi.org/10.1038/s41467-024-44778-2
Johnson, L., & Sarosiek, K. A. (2024). Role of intrinsic apoptosis in environmental exposure health outcomes. Trends in Molecular Medicine, 30(1), 56–73. https://doi.org/10.1016/j.molmed.2023.11.003
Sun, Y., Revach, O.-Y., Anderson, S., Kessler, E. A., Wolfe, C. H., Jenney, A., Mills, C. E., Robitschek, E. J., Davis, T. G. R., Kim, S., Fu, A., Ma, X., Gwee, J., Tiwari, P., Du, P. P., Sindurakar, P., Tian, J., Mehta, A., Schneider, A. M., … Jenkins, R. W. (2023). Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature, 615(7950), 158–167. https://doi.org/10.1038/s41586-023-05704-6
Fröhlich, F., Gerosa, L., Muhlich, J., & Sorger, P. K. (2023). Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance. Molecular Systems Biology, 19(2), e10988. https://doi.org/10.15252/msb.202210988
Ding, L., Wang, Q., Martincuks, A., Kearns, M. J., Jiang, T., Lin, Z., Cheng, X., Qian, C., Xie, S., Kim, H.-J., Launonen, I.-M., Färkkilä, A., Roberts, T. M., Freeman, G. J., Liu, J. F., Konstantinopoulos, P. A., Matulonis, U., Yu, H., & Zhao, J. J. (2023). STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer. Journal for Immunotherapy of Cancer, 11(1), e005627. https://doi.org/10.1136/jitc-2022-005627
Tsvetkov, P., Coy, S., Petrova, B., Dreishpoon, M., Verma, A., Abdusamad, M., Rossen, J., Joesch-Cohen, L., Humeidi, R., Spangler, R. D., Eaton, J. K., Frenkel, E., Kocak, M., Corsello, S. M., Lutsenko, S., Kanarek, N., Santagata, S., & Golub, T. R. (2022). Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 375(6586), 1254–1261. https://doi.org/10.1126/science.abf0529
Oren, Y., Tsabar, M., Cuoco, M. S., Amir-Zilberstein, L., Cabanos, H. F., Hütter, J.-C., Hu, B., Thakore, P. I., Tabaka, M., Fulco, C. P., Colgan, W., Cuevas, B. M., Hurvitz, S. A., Slamon, D. J., Deik, A., Pierce, K. A., Clish, C., Hata, A. N., Zaganjor, E., … Regev, A. (2021). Cycling cancer persister cells arise from lineages with distinct programs. Nature, 596(7873), 576–582. https://doi.org/10.1038/s41586-021-03796-6
Gerosa, L., Chidley, C., Fröhlich, F., Sanchez, G., Lim, S. K., Muhlich, J., Chen, J.-Y., Vallabhaneni, S., Baker, G. J., Schapiro, D., Atanasova, M. I., Chylek, L. A., Shi, T., Yi, L., Nicora, C. D., Claas, A., Ng, T. S. C., Kohler, R. H., Lauffenburger, D. A., … Sorger, P. K. (2020). Receptor-driven ERK pulses reconfigure MAPK signaling and enable persistence of drug-adapted BRAF-mutant melanoma cells. Cell Systems, 11(5), 478-494.e9. https://doi.org/10.1016/j.cels.2020.10.002
Bhola, P. D., Ahmed, E., Guerriero, J. L., Sicinska, E., Su, E., Lavrova, E., Ni, J., Chipashvili, O., Hagan, T., Pioso, M. S., McQueeney, K., Ng, K., Aguirre, A. J., Cleary, J. M., Cocozziello, D., Sotayo, A., Ryan, J., Zhao, J. J., & Letai, A. (2020). High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors. Science Signaling, 13(636). https://doi.org/10.1126/scisignal.aay1451
Melms, J. C., Vallabhaneni, S., Mills, C. E., Yapp, C., Chen, J.-Y., Morelli, E., Waszyk, P., Kumar, S., Deming, D., Moret, N., Rodriguez, S., Subramanian, K., Rogava, M., Cartwright, A. N. R., Luoma, A., Mei, S., Brinker, T. J., Miller, D. M., Spektor, A., … Izar, B. (2020). Inhibition of haspin kinase promotes cell-intrinsic and extrinsic antitumor activity. Cancer Research, 80(4), 798–810. https://doi.org/10.1158/0008-5472.CAN-19-2330
Hemming, M. L., Nathenson, M. J., Lin, J.-R., Mei, S., Du, Z., Malik, K., Marino-Enriquez, A., Jagannathan, J. P., Sorger, P. K., Bertagnolli, M., Sicinska, E., Demetri, G. D., & Santagata, S. (2020). Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1. JCO Precision Oncology, 4, 79–90. https://doi.org/10.1200/po.19.00287
Chopra, S. S., Jenney, A., Palmer, A., Niepel, M., Chung, M., Mills, C., Sivakumaren, S. C., Liu, Q., Chen, J.-Y., Yapp, C., Asara, J. M., Gray, N. S., & Sorger, P. K. (2020). Torin2 exploits replication and checkpoint vulnerabilities to cause death of PI3K-activated triple-negative breast cancer cells. Cell Systems, 10(1), 66-81.e11. https://doi.org/10.1016/j.cels.2019.11.001
Hafner, M., Mills, C. E., Subramanian, K., Chen, C., Chung, M., Boswell, S. A., Everley, R. A., Liu, C., Walmsley, C. S., Juric, D., & Sorger, P. K. (2019). Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chemical Biology, 26(8), 1067-1080.e8. https://doi.org/10.1016/j.chembiol.2019.05.005
Niepel, M., Hafner, M., Mills, C. E., Subramanian, K., Williams, E. H., Chung, M., Gaudio, B., Barrette, A. M., Stern, A. D., Hu, B., Korkola, J. E., LINCS Consortium, Gray, J. W., Birtwistle, M. R., Heiser, L. M., & Sorger, P. K. (2019). A multi-center study on the reproducibility of drug-response assays in mammalian cell lines. Cell Systems, 9(1), 35-48.e5. https://doi.org/10.1016/j.cels.2019.06.005
Jerby-Arnon, L., Shah, P., Cuoco, M. S., Rodman, C., Su, M.-J., Melms, J. C., Leeson, R., Kanodia, A., Mei, S., Lin, J.-R., Wang, S., Rabasha, B., Liu, D., Zhang, G., Margolais, C., Ashenberg, O., Ott, P. A., Buchbinder, E. I., Haq, R., … Regev, A. (2018). A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell, 175(4), 984-997.e24. https://doi.org/10.1016/j.cell.2018.09.006
Fallahi-Sichani, M., Becker, V., Izar, B., Baker, G. J., Lin, J.-R., Boswell, S. A., Shah, P., Rotem, A., Garraway, L. A., & Sorger, P. K. (2017). Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Molecular Systems Biology, 13(1), 905. https://doi.org/10.15252/msb.20166796
Hafner, M., Niepel, M., Chung, M., & Sorger, P. K. (2016). Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. Nature Methods, 13(6), 521–527. https://doi.org/10.1038/nmeth.3853
Spencer, S. L., Gaudet, S., Albeck, J. G., Burke, J. M., & Sorger, P. K. (2009). Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature, 459(7245), 428–432. https://doi.org/10.1038/nature08012
Fitzgerald, J. B., Schoeberl, B., Nielsen, U. B., & Sorger, P. K. (2006). Systems biology and combination therapy in the quest for clinical efficacy. Nature Chemical Biology, 2(9), 458–466. https://doi.org/10.1038/nchembio817

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