Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
Open accessAbstract
Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44(Hi)CD24(Hi) chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Other studies suggest that some persister phenotypes arise via plasticity induced by drug treatment.
“Meanwhile, other studies suggest that some persister phenotypes arise via plasticity induced by drug treatment [56,64,65].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [64]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Siegel, R., Ma, J., Zou, Z., & Jemal, A. (2014) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21208 · Cited by 11,499 · see citing works
Prospective identification of tumorigenic breast cancer cells
Al‐Hajj, M., Wicha, M. S., Benito‐Hernández, A., Morrison, S. J., & Clarke, M. F. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0530291100 · Cited by 10,388 · see citing works
Signet-Ring Cell Carcinoma of the Colon: A Case Report and Review of the Literature
Park, P. Y., Goldin, T. A., Chang, J. C. S., Markman, M. M., & Kundranda, M. N. (2015) · Case Reports in Oncology · doi:10.1159/000441772 · Cited by 5,273 · see citing works
Tumour stem cells and drug resistance
Dean, M., Fojo, T., & Bates, S. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1590 · Cited by 3,668 · see citing works
A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations
Sharma, S. V., Lee, D. Y., Li, B., Quinlan, M. P., Takahashi, F., Maheswaran, S., McDermott, U., Azizian, N., Zou, L., Fischbach, M. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.02.027 · Cited by 2,770 · see citing works
Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening
Gupta, P. B., Önder, T. T., Jiang, G., Tao, K. X., Kuperwasser, C., Weinberg, R. A., & Lander, E. S. (2009) · Cell · doi:10.1016/j.cell.2009.06.034 · Cited by 2,393 · see citing works
Intra-tumour heterogeneity: a looking glass for cancer?
Marusyk, A., Almendro, V., & Polyák, K. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3261 · Cited by 2,003 · see citing works
Mutation selection and the natural history of cancer
Cairns, J. (1975) · Nature · doi:10.1038/255197a0 · Cited by 1,592 · see citing works
Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells
Gupta, P. B., Fillmore, C. M., Jiang, G., Shapira, S. D., Tao, K., Kuperwasser, C., & Lander, E. S. (2011) · Cell · doi:10.1016/j.cell.2011.07.026 · Cited by 1,475 · see citing works
Molecular Definition of Breast Tumor Heterogeneity
Shipitsin, M. V., Campbell, L. L., Argani, P., Weremowicz, S., Bloushtain-Qimron, N., Yao, J., Nikolskaya, T., Serebryiskaya, T., Beroukhim, R., Hu, M., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.01.013 · Cited by 1,358 · see citing works
Brainson, C. F., & Kuperwasser, C. (2008) · Breast Cancer Research · doi:10.1186/bcr1982 · Cited by 1,035 · see citing works
von Minckwitz, G., Schneeweiß, A., Loibl, S., Salat, C., Denkert, C., Rezai, M., Blohmer, J., Jackisch, C., Paepke, S., Gerber, B., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70160-3 · Cited by 1,025 · see citing works
Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system
Sengupta, S., Eavarone, D. A., Capila, I., Zhao, G., Watson, N., Kiziltepe, T., & Sasisekharan, R. (2005) · Nature · doi:10.1038/nature03794 · Cited by 946 · see citing works
Self-citationLee, M. J., Ye, A. S., Gardino, A. K., Heijink, A. M., Sorger, P. K., MacBeath, G., & Yaffe, M. B. (2012) · Cell · doi:10.1016/j.cell.2012.03.031 · Cited by 681 · see citing works
Tyr 527 Is Phosphorylated in pp60 c- src : Implications for Regulation
Cooper, J. A., Gould, K. L., Cartwright, C. A., & Hunter, T. R. (1986) · Science · doi:10.1126/science.2420005 · Cited by 540 · see citing works
Pegram, M. D., Konecny, G., O'Callaghan, C. J., Beryt, M., Pietras, R. J., & Slamon, D. J. (2004) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djh131 · Cited by 513 · see citing works
Swanton, C., Marani, M., Pardo, O. E., Warne, P. H., Kelly, G. P., Sahai, E. A., Elustondo, F., Chang, J. C., Temple, J., Ahmed, A. A., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.04.011 · Cited by 381 · see citing works
Endoreplication and polyploidy: insights into development and disease
Fox, D. T., & Duronio, R. J. (2013) · Development · doi:10.1242/dev.080531 · Cited by 331 · see citing works
Majumder, B., Ulaganathan, B., Thiyagarajan, S., Radhakrishnan, P., Narasimhan, H., Dhandapani, M., Brijwani, N., Pinto, D. D., Prasath, A., Shanthappa, B., et al. (2015) · Nature Communications · doi:10.1038/ncomms7169 · Cited by 307 · see citing works
Self-citationCD24 expression is a new prognostic marker in breast cancer.
Kristiansen, G., Winzer, K., Mayordomo, É., Bellach, J., Schlüns, K., Denkert, C., Dahl, E., Pilarsky, C. P., Altevogt, P., Guski, H., et al. (2003) · PubMed · Cited by 306 · see citing works
Non-Darwinian dynamics in therapy-induced cancer drug resistance
Pisco, A. O., Brock, A., Zhou, J., Moor, A. E., Mojtahedi, M., Jackson, D. A., & Huang, S. (2013) · Nature Communications · doi:10.1038/ncomms3467 · Cited by 289 · see citing works
Specific Growth Rate versus Doubling Time for Quantitative Characterization of Tumor Growth Rate
Mehrara, E., Forssell-Aronsson, E. B., Ahlman, H., & Bernhardt, P. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3822 · Cited by 247 · see citing works
Regulation of Src Family Kinases in Human Cancers
Sen, B., & Johnson, F. M. (2011) · Journal of Signal Transduction · doi:10.1155/2011/865819 · Cited by 231 · see citing works
Dasatinib as a Single Agent in Triple-Negative Breast Cancer: Results of an Open-Label Phase 2 Study
Finn, R. S., Bengala, C., Ibrahim, N. K., Roche, H. H., Sparano, J. A., Strauss, L. C., Fairchild, J. P., Sy, O., & Goldstein, L. J. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0288 · Cited by 220 · see citing works
Decline in the Use of Anthracyclines for Breast Cancer
Giordano, S. H., Lin, Y.-L., Kuo, Y., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.40.1273 · Cited by 192 · see citing works
Caveolin-1 Potentiates Estrogen Receptor α (ERα) Signaling
Schlegel, A., Wang, C., Katzenellenbogen, B. S., Pestell, R. G., & Lisanti, M. P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.47.33551 · Cited by 156 · see citing works
Resistance mechanisms to cancer chemotherapy
Redmond, K. M. (2008) · Frontiers in bioscience · doi:10.2741/3070 · Cited by 150 · see citing works
Dasatinib combined with docetaxel for castration‐resistant prostate cancer
Araujo, J. C., Mathew, P. F., Armstrong, A. J., Braud, E. L., Posadas, E. M., Lonberg, M., Gallick, G. E., Trudel, G. C., Paliwal, P., Agrawal, S., et al. (2011) · Cancer · doi:10.1002/cncr.26204 · Cited by 149 · see citing works
p73 induces apoptosis by different mechanisms
Ramadan, S. M., Terrinoni, A., Catani, M. V., Sayan, E., Knight, R. A., Mueller, M., Krammer, P. H., Melino, G., & Candi, E. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.156 · Cited by 145 · see citing works
Do β-tubulin mutations have a role in resistance to chemotherapy?
Berrieman, H. K., Lind, M., & Cawkwell, L. (2004) · The Lancet Oncology · doi:10.1016/s1470-2045(04)01411-1 · Cited by 141 · see citing works
Tunggal, J. K., Cowan, D., Shaikh, H., & Tannock, I. F. (1999) · PubMed · Cited by 133 · see citing works
“Persisters”: Survival at the Cellular Level
Dawson, C. C., Intapa, C., & Jabra‐Rizk, M. A. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002121 · Cited by 119 · see citing works
CpG island shore methylation regulates caveolin-1 expression in breast cancer
Rao, X., Evans, J. M., Chae, H., Pilrose, J. M., Kim, S., Yan, P. S., Huang, R.-L., Lai, H.-C., Lin, H.-J. L., Liu, Y., et al. (2012) · Oncogene · doi:10.1038/onc.2012.474 · Cited by 117 · see citing works
CD44 Engagement Promotes Matrix-Derived Survival through the CD44-SRC-Integrin Axis in Lipid Rafts
Lee, J.-L., Wang, M.-J., Sudhir, P., & Chen, J.-Y. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00186-08 · Cited by 114 · see citing works
Finding the tumor copycat: Therapy fails, patients don’t
Ellis, L. M., & Fidler, I. J. (2010) · Nature Medicine · doi:10.1038/nm0910-974 · Cited by 109 · see citing works
A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo
Saito, Y., Yuki, H., Kuratani, M., Hashizume, Y., Takagi, S., Honma, T., Tanaka, A., Shirouzu, M., Mikuni, J., Handa, N., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3004387 · Cited by 94 · see citing works
Yoo, S.-H., Park, Y. S., Kim, H.-R., et al. (2003) · Lung Cancer · doi:10.1016/s0169-5002(03)00287-3 · Cited by 93 · see citing works
Herold, C. I., Chadaram, V., Peterson, B. L., Marcom, P. K., Hopkins, J. O., Kimmick, G. G., Favaro, J., Hamilton, E. P., Welch, R. A., Bacus, S. S., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1071 · Cited by 90 · see citing works
Cara, S., & Tannock, I. F. (2001) · Annals of Oncology · doi:10.1023/a:1008389706725 · Cited by 85 · see citing works
Bretz, N. P., Noske, A., Keller, S., Erbe-Hoffmann, N., Schlange, T., Salnikov, A. V., Moldenhauer, G., Kristiansen, G., & Altevogt, P. (2011) · Clinical & Experimental Metastasis · doi:10.1007/s10585-011-9426-4 · Cited by 66 · see citing works
Lyn is involved in CD24-induced ERK1/2 activation in colorectal cancer
Su, N., Peng, L., Xia, B., Zhao, Y., Xu, A., Wang, J., Wang, X., & Jiang, B. (2012) · Molecular Cancer · doi:10.1186/1476-4598-11-43 · Cited by 64 · see citing works
Baumann, P., Thiele, W., Cremers, N., Muppala, S., Krachulec, J., Diefenbacher, M. E., Kassel, O., Mudduluru, G., Allgayer, H., Frame, M. C., et al. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0756-9 · Cited by 63 · see citing works
Cabazitaxel, a new taxane with favorable properties
Bouchet, B. P., & Galmarini, C. M. (2010) · Drugs of today · doi:10.1358/dot.2010.46.10.1519019 · Cited by 54 · see citing works
Expression of caveolin-1 in pleomorphic carcinoma of the lung is correlated with a poor prognosis.
Moon, K. C., Lee, G. K., Yoo, S.-H., et al. (2006) · PubMed · Cited by 40 · see citing works
Regulation of p73 by Hck through kinase-dependent and independent mechanisms
Paliwal, P., Radha, V., & Swarup, G. (2007) · BMC Molecular Biology · doi:10.1186/1471-2199-8-45 · Cited by 34 · see citing works
The interrelationships between Src, Cav-1 and RhoGD12 in transitional cell carcinoma of the bladder
Qayyum, T., Fyffe, G., Duncan, M., McArdle, P., Hilmy, M., Orange, C., Halbert, G., Seywright, M. M., Horgan, P. G., Underwood, M. A., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.52 · Cited by 21 · see citing works
Nelli, F., Moscetti, L. I., Natoli, G., et al. (2012) · International Journal of Clinical Oncology · doi:10.1007/s10147-012-0384-x · Cited by 17 · see citing works
Million, K., Horvilleur, E., Goldschneider, D., AGINA, M. D. M. A. E.-K. H. A., Raguénez, G., Tournier, F., Bénard, J., & Douc‐Rasy, S. (2006) · International Journal of Oncology · doi:10.3892/ijo.29.1.147 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Cancer stem cells as key drivers of tumour progression
Ayob, A. Z., & Ramasamy, T. S. (2018) · Journal of Biomedical Science · doi:10.1186/s12929-018-0426-4 · Cited by 910 · see citing works
Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer
Cabanos, H. F., & Hata, A. N. (2021) · Cancers · doi:10.3390/cancers13112666 · Cited by 189 · see citing works
Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer
Risom, T., Langer, E. M., Chapman, M. P., Rantala, J., Fields, A. J., Boniface, C., Alvarez, M. J., Kendsersky, N. D., Pelz, C. R., Johnson-Camacho, K., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05729-w · Cited by 174 · see citing works
Role of vascular normalization in benefit from metronomic chemotherapy
Mpekris, F., Baish, J. W., Stylianopoulos, T., & Jain, R. K. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700340114 · Cited by 178 · see citing works
Cancer Stem Cells and Epithelial-to-Mesenchymal Transition in Cancer Metastasis
Celià-Terrassa, T., & Jolly, M. K. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a036905 · Cited by 163 · see citing works
Targeting tumour microenvironment by tyrosine kinase inhibitor
Tan, H.-Y., Wang, N., Lam, W., Guo, W., Feng, Y., & Cheng, Y.-C. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0800-6 · Cited by 107 · see citing works
Multiplexed drug testing of tumor slices using a microfluidic platform
Horowitz, L. F., Rodriguez, A. D., Dereli-Korkut, Z., Lin, R., Castro, K., Mikheev, A. M., Monnat, R. J., Folch, A., & Rostomily, R. C. (2020) · npj Precision Oncology · doi:10.1038/s41698-020-0117-y · Cited by 88 · see citing works
Dynamic Microenvironment Induces Phenotypic Plasticity of Esophageal Cancer Cells Under Flow
Calibasi Kocal, G., Güven, S., Foygel, K., Goldman, A., Chen, P., Sengupta, S., Paulmurugan, R., Baskin, Y., & Demirci, U. (2016) · Scientific Reports · doi:10.1038/srep38221 · Cited by 52 · see citing works
Self-citation
- Authors
- Goldman, A., Majumder, B., Dhawan, A., Ravi, S., Goldman, D., Kohandel, M., Majumder, P. K., & Sengupta, S.
- Affiliations
- Brigham and Women's Hospital (US)
- Mitra Biotech (India) (IN)
- Queen's University (CA)
- University of Waterloo (CA)
- Corresponding author
- Goldman, Aaron
- Sengupta, Shiladitya
- ORCID
- Venue
- Nature Communications
- Published
- 2015-02-11
- Volume
- 6
- Issue
- 1
- Pages
- 6139-6139
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4339891
- OpenAlex
- W2081820338
- Cited by
- 260
- References
- 49
- Citations by year
- 2026: 5 · 2025: 24 · 2024: 14 · 2023: 18 · 2022: 19 · 2021: 27 · 2020: 31 · 2019: 36 · 2018: 30 · 2017: 26 · 2016: 21 · 2015: 9
- FWCI
- 12.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Indo-US Science and Technology Forum
- Servier
- National Institutes of Health (W81XWH)
- Natural Sciences and Engineering Research Council of Canada
- National Cancer Institute (R01CA135242, R21CA186009)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- adaptive drug resistance, chemoresistance, breast cancer, taxanes, CD44, CD24, lipid rafts, Src family kinases, Hck, apoptosis inhibition, kinase inhibitors, chemosensitization
- MeSH terms
- Animals, Antineoplastic Agents, Bridged-Ring Compounds, Drug Evaluation, Preclinical, Female, Humans, Mice, Inbred BALB C, Models, Biological, Neoplasms, Phenotype, Time Factors, Neoplastic Stem Cells, Signal Transduction, Antigens, CD, Drug Resistance, Neoplasm, Membrane Microdomains, Taxoids, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Carcinogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
