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Review

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

by
Svetlana N. Aleksakhina
1,
Alexander O. Ivantsov
1,2 and
Evgeny N. Imyanitov
1,2,*
1
Department of Tumor Growth Biology, N. N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia
2
Department of Medical Genetics, St. Petersburg Pediatric Medical University, 194100 St. Petersburg, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(7), 4094; https://doi.org/10.3390/ijms25074094
Submission received: 18 February 2024 / Revised: 27 March 2024 / Accepted: 3 April 2024 / Published: 7 April 2024
(This article belongs to the Special Issue Innovative Approaches for Targeted Cancer Therapies)

Abstract

Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.
Keywords: agnostic markers; targeted therapy; microsatellite instability; TMB; HRD; kinase inhibitors agnostic markers; targeted therapy; microsatellite instability; TMB; HRD; kinase inhibitors
Graphical Abstract

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MDPI and ACS Style

Aleksakhina, S.N.; Ivantsov, A.O.; Imyanitov, E.N. Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution. Int. J. Mol. Sci. 2024, 25, 4094. https://doi.org/10.3390/ijms25074094

AMA Style

Aleksakhina SN, Ivantsov AO, Imyanitov EN. Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution. International Journal of Molecular Sciences. 2024; 25(7):4094. https://doi.org/10.3390/ijms25074094

Chicago/Turabian Style

Aleksakhina, Svetlana N., Alexander O. Ivantsov, and Evgeny N. Imyanitov. 2024. "Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution" International Journal of Molecular Sciences 25, no. 7: 4094. https://doi.org/10.3390/ijms25074094

APA Style

Aleksakhina, S. N., Ivantsov, A. O., & Imyanitov, E. N. (2024). Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution. International Journal of Molecular Sciences, 25(7), 4094. https://doi.org/10.3390/ijms25074094

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