Anticancer drug resistance: An update and perspective

Abstract

Driver mutations promote initiation and progression of cancer. Pharmacological treatment can inhibit the action of the mutant protein; however, drug resistance almost invariably emerges. Multiple studies revealed that cancer drug resistance is based upon a plethora of distinct mechanisms. Drug resistance mutations can occur in the same protein or in different proteins; as well as in the same pathway or in parallel pathways, bypassing the intercepted signaling. The dilemma that the clinical oncologist is facing is that not all the genomic alterations as well as alterations in the tumor microenvironment that facilitate cancer cell proliferation are known, and neither are the alterations that are likely to promote metastasis. For example, the common KRas^G12C driver mutation emerges in different cancers. Most occur in NSCLC, but some occur, albeit to a lower extent, in colorectal cancer and pancreatic ductal carcinoma. The responses to KRas^G12C inhibitors are variable and fall into three categories, (i) new point mutations in KRas, or multiple copies of KRAS G12C which lead to higher expression level of the mutant protein; (ii) mutations in genes other than KRAS; (iii) original cancer transitioning to other cancer(s). Resistance to adagrasib, an experimental antitumor agent exerting its cytotoxic effect as a covalent inhibitor of the G12C KRas, indicated that half of the cases present multiple KRas mutations as well as allele amplification. Redundant or parallel pathways included MET amplification; emerging driver mutations in NRAS, BRAF, MAP2K1, and RET; gene fusion events in ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN tumor suppressors. In the current review we discuss the molecular mechanisms underlying drug resistance while focusing on those emerging to common targeted cancer drivers. We also address questions of why cancers with a common driver mutation are unlikely to evolve a common drug resistance mechanism, and whether one can predict the likely mechanisms that the tumor cell may develop. These vastly important and tantalizing questions in drug discovery, and broadly in precision medicine, are the focus of our present review. We end with our perspective, which calls for target combinations to be selected and prioritized with the help of the emerging massive compute power which enables artificial intelligence, and the increased gathering of data to overcome its insatiable needs.

Keywords: Cancer; Chemotherapy; Chromatin accessibility; Drug discovery; Drug resistance; Epigenetics; Interactome; MAPK; Precision medicine; Single cell; Transcriptomics.

Figure 1

The role of heterogeneity in drug resistance. An example of cells in the tissue containing a vast number of common driver mutant (e.g., KRas4B G12C) and a small number of rare drug resistance mutant cells (lower left). When a drug is taken, all cells are decimated except those with rare resistance mutation for the particular drug, resulting that those cells with the rare mutation proliferate (middle). A subsequent drug will remove the rare drug resistance mutant cells in later stage of chemotherapy (lower right). However, simultaneously taking both drugs have a better chance of success.

Figure 2

The mechanism of KRas4B^G12C drug resistance. Examples of covalent drugs, adagrasib (MRTX849) and sotorasib (AMG510), bound to Cys12 of GDP-bound KRas4B (upper panel). The outcomes of drug resistance for a common driver mutation G12C in KRas4B (lower panel).

Figure 3

Inhibitors for Bcr-Abl fusion tyrosine kinase. Molecular structures of the drugs bound to the kinase domain of Abl (upper panel). Orthosteric ATP-competitive drugs, such as imatinib (STI571), nilotinib (AMN107), dasatinib (BMS-354825), and ponatinib (AP24534), can inhibit oncogenic Bcr-Abl kinase activity. However, drug resistance mutations in ATP-binding site, such as gatekeeper mutation T315I (Abl1 isoform IA; T334I for Abl1 isoform IB), or the activation loop can change conformation of the active site, preventing the orthosteric drugs from the oncogenic inhibition. Allosteric drugs bound to the myristate pocket, such as GNF-2, GNF-5 and asciminib (ABL001), can re-sensitize the orthosteric drugs, overcoming the drug resistant. Drug structures were obtained from PubChem (https://pubchem.ncbi.nlm.nih.gov), a public chemical database at the National Library of Medicine (NLM) (Kim et al., 2021). Examples shown for the crystal structures of Abl1 autoinhibition, drug-bound kinase domains, and drug-induced Abl1 autoinhibition (lower panels).