Chemical Reviews pubs.acs.
org/CR Review
Figure 2. Central nervous system multiparameter optimization (MPO) desirability score to guide the optimization of blood−brain barrier
permeability. Reproduced from ref 53. Copyright 2016 American Chemical Society.
enabled the clinical use of a broad range of cancer detection 2. MECHANISMS OF DRUG RESISTANCE IN CANCER
and diagnosis assays as part of patient treatment.42 There is a wide range of mechanisms to which cancer cells are
When early potential cancer drugs were first evaluated in inherently resistant, or acquire resistance, to drug therapies.
clinical trials, the specific type of cancer to target was These mechanisms can impact the drug molecule itself or have
commonly driven by protein expression or activity in an effect on the target of the drug. Some of the most common
preclinical xenograft models.43 As our understanding of the mechanisms observed in the treatment of cancer patients are
genetic drivers of cancer has increased, this has enabled drug highlighted briefly in the following sections. Later sections
discovery scientists to identify drug molecules with improved such as the case studies in section 3 will give additional
efficacy and safety profiles as cancers can be targeted more information on the various strategies that have been
specifically. This ability of being able to match each patient or implemented to target these mechanisms of resistance with
disease to the most appropriate drug, or drug combinations, is additional drug discovery approaches.
commonly referred to as “personalized medicine”.44 Genetic
drivers that offer the potential of increased growth and survival 2.1. Increased Drug Efflux
for a tumor are commonly referred to as “oncogenes”.45 One of the most direct methods in which tumors can become
In a landmark publication from Hanahan and Weinberg in resistant to drug treatment is via physical mechanisms to block,
2000, they described six “biological capabilities” or “hallmarks” or limit, the access of the drug to the site of action. One such
which are commonly acquired during the development of mechanism is through increased expression of the ATP-
tumors.46 These were sustained proliferative signaling, evading binding cassette (ABC) transporter family proteins, known to
growth suppressors, inducing angiogenesis, resisting cell death, play a role in multidrug resistance (MDR), such as MDR1 (P-
enabling replicative immortality, and activating invasion and glycoprotein) and multidrug resistance proteins (MRPs) or
metastasis. In 2011, due to further progress in the under- brain cancer resistance proteins (BCRPs).48 These proteins act
standing of cancer, Hanahan and Weinberg added two as cell membrane pumps that are effectively capable of
emerging hallmarks to this list, namely the reprogramming of removing the drug from cancer cells, and consequently,
energy metabolism and the ability to evade immune overexpression of these transporters has been widely associated
destruction.47 In addition, the authors recognized that the with poor patient outcomes across many different tumors. An
biology of tumors can no longer be understood simply by effective intracellular drug molecule must not only be able to
enumerating the traits of the cancer cells but instead must pass through cell membranes but also remain in the cell
encompass the contributions of the “tumor microenvironment” through the avoidance of such efflux transporters. In cases
to tumorigenesis (Figure 1). where efflux transporters are overexpressed a number of cancer
In this complex environment the cancer can thrive in the drugs have been shown to be less effective across multiple
context of acquired mutations, translocations, and copy tumor types, especially chemotherapy-based agents such as
number variations (CNVs). Genomic instability in tumors is vinblastine, vincristine, doxorubicin, daunorubicin, and pacli-
therefore very common together with a high degree of tumor taxel.49 There have been ongoing efforts to therapeutically
heterogeneity, which is the observation that different tumor target these transporters to circumvent this mechanism of
cells can show different morphological and phenotypic profiles. resistance, but targeting these transporters with the required
This heterogeneity can be intratumoral (within a primary level of selectivity is challenging.50
tumor), intermetastatic (between two metastases), intra- An additional impact of this mechanism of resistance to
metastatic (within metastatic lesions), or interpatient, and targeted cancer therapies has been reported where the tumor
this further increases the complexity of targeted cancer metastasizes to the central nervous system (CNS) and or the
treatments. As these hallmarks of cancer have become brain of a patient.51 This can be a highly effective mechanism
increasingly understood, an important focus has become the of resistance as the majority of cancer drug treatments cannot
understanding of the resistance of cancers to therapeutic effectively cross the blood−brain barrier (BBB), which is
treatments, which will be covered in section 2. highly populated with MDR1 and BCRP transporters. There
D https://dx.doi.org/10.1021/acs.chemrev.0c00383
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