Challenges and Opportunities in Cancer Drug Resistance

Abstract

There has been huge progress in the discovery of targeted cancer therapies in recent years. However, even for the most successful and impactful cancer drugs which have been approved, both innate and acquired mechanisms of resistance are commonplace. These emerging mechanisms of resistance have been studied intensively, which has enabled drug discovery scientists to learn how it may be possible to overcome such resistance in subsequent generations of treatments. In some cases, novel drug candidates have been able to supersede previously approved agents; in other cases they have been used sequentially or in combinations with existing treatments. This review summarizes the current field in terms of the challenges and opportunities that cancer resistance presents to drug discovery scientists, with a focus on small molecule therapeutics. As part of this review, common themes and approaches have been identified which have been utilized to successfully target emerging mechanisms of resistance. This includes the increase in target potency and selectivity, alternative chemical scaffolds, change of mechanism of action (covalents, PROTACs), increases in blood−brain barrier permeability (BBBP), and the targeting of allosteric pockets. Finally, wider approaches are covered such as monoclonal antibodies (mAbs), bispecific antibodies, antibody drug conjugates (ADCs), and combination therapies.

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

“…The designing of PROTACs has different limitations, including problems in isolation, reduced cell permeability, and off-target toxicity effects due to a low therapeutic index [ 22 , 23 , 24 ]. PROTACs act in a catalytic mode, which hampers their pharmacokinetic and pharmacodynamic evaluation.…”

Peptides as a platform for targeted therapeutics for cancer: peptide–drug conjugates (PDCs)

“…Following treatment with all of these drugs, cancers may further mutate to develop resistance to targeted therapies; these resistance mutations provide challenges but also new opportunities for drug discovery. 24 Antibody-drug conjugates (ADCs) are another promising line of targeted therapy composed of an antibody which binds to a protein highly expressed in tumour cells (a tumour antigen), connected via a linker to a cytotoxic small molecule payload. In principle, this design enables the targeted delivery of a drug to the tumour, killing cancer cells while sparing healthy tissue and providing a wider therapeutic margin than traditional chemotherapy.…”

Recent Progress of Alkyl Radicals Generation‐Based Agents for Biomedical Applications

“…[1][2][3][4][5] Existing treatment methods mainly include surgery, chemotherapy, radiotherapy, etc. [6][7][8][9] While surgery is an extensively used approach, it is quite difficult to completely clear tumor and the uncleared tumor tissue can lead to recurrence. [10,11] Chemotherapy uses chemotherapeutic drugs to kill cancer cells.…”