Precision oncology provides opportunities for targeting KRAS-inhibitor resistance
Open accessAbstract
in various cancers have shown good initial efficacy, but therapy-related drug resistance eventually occurs in most patients. It has become apparent that cancer cells not only rely on novel mutations that provide escape mechanisms, but about half of them become resistant in the absence of apparent genetic mutations. Redundancies within the KRAS signaling pathways and cross-talk between these pathways - as well as other canonical cancer-driving mechanisms - not only provide challenges but also present opportunities for drug development and targeted approaches. We discuss the challenges for the duality of KRAS inhibitor drug resistance with an additional focus on nongenetic mechanisms and the potential for patient-centered combination treatments.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
A significant challenge with KRAS inhibitors is that the majority of patients do not respond, and initial responders will inevitably encounter disease progression.
“Furthermore, a significant challenge with KRAS inhibitors is that the majority of patients do not respond to such treatments, and initial responders will inevitably encounter disease progression. 9-12”
From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [10]
Cites
Hallmarks of Cancer: New Dimensions
Hanahan, D. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1059 · Cited by 9,887 · see citing works
The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity
Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1694-1 · Cited by 2,277 · see citing works
RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943 · see citing works
Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation
Skoulidis, F., Li, B. T., Dy, G. K., Price, T. J., Falchook, G. S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., Barlesi, F., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2103695 · Cited by 1,849 · see citing works
Hallin, J., Engstrom, L. D., Hargis, L., Calinisan, A., Aranda, R., Briere, D. M., Sudhakar, N., Bowcut, V., Baer, B. R., Ballard, J. A., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1167 · Cited by 1,304 · see citing works
Acquired Resistance to KRAS <sup>G12C</sup> Inhibition in Cancer
Awad, M. M., Liu, S., Rybkin, I. I., Arbour, K. C., Dilly, J., Zhu, V. W., Johnson, M. L., Heist, R. S., Patil, T., Riely, G. J., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2105281 · Cited by 1,247 · see citing works
Adagrasib in Non–Small-Cell Lung Cancer Harboring a <i> KRAS <sup>G12C</sup> </i> Mutation
Jänne, P. A., Riely, G. J., Gadgeel, S. M., Heist, R. S., Ou, S.-H. I., Pacheco, J. M., Johnson, M. L., Sabari, J. K., Leventakos, K., Yau, E., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2204619 · Cited by 1,061 · see citing works
Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations
Hunter, J. C., Manandhar, A., Carrasco, M. A., Gurbani, D., Gondi, S., & Westover, K. D. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0203 · Cited by 786 · see citing works
Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state
Patricelli, M. P., Janes, M. R., Li, L.-S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., Ely, T., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1105 · Cited by 759 · see citing works
Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Lito, P., Solomon, M., Li, L.-S., Hansen, R., & Rosen, N. (2016) · Science · doi:10.1126/science.aad6204 · Cited by 691 · see citing works
Tanaka, N., Lin, J. J., Li, C., Ryan, M. B., Zhang, J., Kiedrowski, L. A., Michel, A. G., Syed, M. U., Fella, K. A., Sakhi, M., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0365 · Cited by 527 · see citing works
Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition
Ryan, M. B., Fece de la Cruz, F., Phat, S., Myers, D. T., Wong, E., Shahzade, H. A., Hong, C. B., & Corcoran, R. B. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3523 · Cited by 496 · see citing works
Diverse alterations associated with resistance to KRAS(G12C) inhibition
Zhao, Y., Murciano-Goroff, Y. R., Xue, J. Y., Ang, A., Lucas, J., Mai, T. T., Da Cruz Paula, A. F., Saiki, A. Y., Mohn, D., Achanta, P., et al. (2021) · Nature · doi:10.1038/s41586-021-04065-2 · Cited by 479 · see citing works
FDA Approval Summary: Sotorasib for <i>KRAS G12C</i> -Mutated Metastatic NSCLC
Nakajima, E. C., Drezner, N., Li, X., Mishra-Kalyani, P. S., Liu, Y., Zhao, H., Bi, Y., Liu, J., Rahman, A., Wearne, E., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-3074 · Cited by 333 · see citing works
Regulation of TEAD Transcription Factors in Cancer Biology
Huh, H., Kim, D., Jeong, H.-S., & Park, H. (2019) · Cells · doi:10.3390/cells8060600 · Cited by 259 · see citing works
Weiss, A., Lorthiois, E., Barys, L., Beyer, K. S., Bomio-Confaglia, C., Burks, H., Chen, X., Cui, X., de Kanter, R., Dharmarajan, L., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0158 · Cited by 150 · see citing works
Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition
Tsai, Y. S., Woodcock, M. G., Azam, S. H., Thorne, L. B., Kanchi, K. L., Parker, J. S., Vincent, B. G., & Pecot, C. V. (2022) · Journal of Clinical Investigation · doi:10.1172/jci155523 · Cited by 103 · see citing works
Weiss, J., Yaeger, R. D., Johnson, M. L., Spira, A., Klempner, S. J., Barve, M. A., Christensen, J. G., Chi, A., Der-Torossian, H., Velastegui, K., et al. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.08.2093 · Cited by 73 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Zhou, C., Li, C., Luo, L., Li, X., Jia, K., He, N., Mao, S., Wang, W., Shao, C., Liu, X., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.06.001 · Cited by 102 · see citing works
Kang, D., Wang, Y., Lin, Y., Ma, W. W., Morgensztern, D., Leventakos, K., Bi, C., Ding, Y., Xiong, J., Yan, M., et al. (2025) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-3691 · Cited by 17 · see citing works
- Authors
- Sattler, M., Mohanty, A., Kulkarni, P., & Salgia, R.
- Affiliations
- Harvard University (US)
- City Of Hope National Medical Center (US)
- Corresponding author
- Salgia, Ravi
- Venue
- Trends in Cancer
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 9
- Issue
- 1
- Pages
- 42-54
- ISSN
- 2405-8025 (ISSN-L)
- 2405-8033
- OpenAlex
- W4307467093
- Cited by
- 54
- References
- 18
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 13 · 2023: 13
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Trends in cancer (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- KRAS inhibitors, drug resistance, precision oncology, pathway crosstalk, combination therapy, patient-centered treatment
- MeSH terms
- Cross Reactions, Humans, Medical Oncology, Neoplasms, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Precision Medicine
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
