Taking on the challenge of cancer drug resistance

Tumour survival, growth, and proliferation demand complex and broad biological capabilities, including proliferative signalling, evasion of growth suppressors, promotion of local blood vessel formation, resistance to cell death, replicative immortality, invasion and metastasis, reprogramming of energy metabolism, and evasion of immune destruction. Tumours are morphologically and phenotypically heterogenous and genetically unstable, exhibiting acquired mutation, gene translocation, and differences in copy number.

Inherent plasticity and adaptability allow tumours to muster multiple mechanisms, which can act independently or in concert to thwart the actions of cytotoxic, anti-metabolic, or molecularly targeted chemotherapy. Primary or innate resistance may involve: mutation; genetic heterogeneity, giving rise to subpopulations of intrinsically resistant cells, such as cancer stem cells; or through drug inactivation or detoxification by enzyme action. Acquired or secondary resistance results from an alteration in drug targets through mutation, changes in target expression, activation of non-target oncogenes, metabolic change, increased transport of the drug out of the cell, and alteration of signalling pathways through epigenetic change.

Promising strategies to overcome resistance

Combination therapy can reduce the probability of resistance by simultaneously targeting different tumour vulnerabilities. Early detection and judicious treatment choice have dramatically improved survival rates for some cancers, but resistance is estimated to contribute to 90% of treatment failures in those with advanced disease. The impact of adaptive or intermittent chemotherapy on the emergence of acquired resistance remains to be established.

Over 20 years ago, the approval of imatinib, the first cancer drug designed to target an aberrant critical signalling pathway identified in chronic myeloid leukaemia, heralded the arrival of orally dosed small molecule agents specific for targets present only in tumour cells and with low toxicity for normal cells. Subsequent generations of tyrosine kinase inhibitors have made previously untreatable cancers, such as metastatic melanoma and Non-Small Cell Lung Cancer (NSCLC), treatable, but high initial response rates are generally short-lived, due to the emergence of point mutations, which alter target protein composition or expression.

Targeting efflux and epigenetic alterations

Efflux, the pumping out of cancer drugs, confers multidrug resistance. Inhibition of the proteins – which mediate efflux, the ABC (ATP-Binding Cassette) transporters, especially the multidrug resistance protein MDR1, also known as P-glycoprotein or P-gp – has been widely explored as a means of restoring cancer drug efficacy. First-generation inhibitors, such as verapamil, quinidine, amiodarone, and cyclosporin A, all failed due to low potency or toxicity when added to existing chemotherapy regimens. Later agents demonstrated off-target effects, such as inhibition of cytochrome P450 or inhibition of ABC transporters essential to normal cell function.

Interest in efflux modulation has returned with a fuller understanding of the genetics and function of the ABC transporter family and the identification of two further ABC transporters associated with multidrug resistance. SCO-101 (Scandion Oncology), a small molecule inhibitor of the transporter protein ABCG2, is under early clinical evaluation as an add-on to chemotherapy in patients with advanced colorectal and pancreatic cancer.

Epigenetic alteration, the switching off or on of gene expression through DNA methylation or acetylation or by modification of the histone proteins, which pack chromosomes into a compact form, is a key mechanism in multidrug resistance. Hypermethylation in the promoter regions of tumour suppressor genes correlates with resistance to cytotoxic, radiation, and biologic therapy in solid tumours.

test tubes

Acquired resistance in ovarian cancer is associated with increased levels of methylation close to the hMLH1 gene, which encodes a protein necessary for DNA mismatch repair. Decitabine, a generic DNA methylation inhibitor indicated in myelodysplastic syndrome, can restore platinum sensitivity in ovarian cancer xenografts. Another DNA methylation inhibitor, guadecitabine (SGI-110: Astex/Otsuka), also holds promise in the restoration of platinum drug sensitivity.

Non-coding microRNAs also contribute to epigenetic alteration, through inhibition of DNA transmethylases and histone deacetylases, and a variety of miRNAS are associated with the regulation of resistance in several different solid tumour types. There is much interest in the therapeutic potential of miRNA targeting, although practicalities that need to be addressed include effective delivery to the site of action, the limited stability of miRNAs, and the potential for off-target effects.

Many of the major signalling pathways that are deregulated in cancers – RAS–MAPK, PI3K–AKT–mTOR, MYC, and WNT–β-catenin – lead to activation and over-expression of the initiation factor 4F (eIF4F) complex. Importantly, inhibition of eIF4F selectively affects the translation of a small number of mRNAs that mainly code for proteins involved in oncogenic events, such as cyclin-D1 and c-MYC, which drive tumour growth and facilitate acquired resistance. Housekeeping genes are not affected, suggesting that eIF4F inhibitors may be cytotoxic to cancer cells and not to normal cells.

Emerging approaches

Ribonexus is developing orally available synthetic small molecule drugs modelled on flavaglines, naturally occurring and highly potent eIF4A inhibitors. These compounds are expected to be used in combination with standard-of-care treatments; in vitro studies have established that candidate inhibitors prevent the proliferation of tyrosine kinase inhibitor-resistant solid tumour cell lines and the translation of key drivers of tumour growth.

Promising clinical data has recently been reported for the eIF4A inhibitor zotatifin (eFFector Therapeutics) when administered in combination with chemotherapy in heavily pre-treated breast cancer patients. Circulating DNA analysis found mutations associated with resistance to endocrine therapy to be decreased or eliminated following zotatifin treatment.

Another strategy with broad potential in overcoming resistance is through targeted protein degradation by PROteolysis TArgeting Chimeras (PROTACs) – bifunctional small molecules able to selectively induce degradation via the ubiquitin–proteasome system. PROTACS act by hijacking their protein target and binding it to a joined E3 ligand. This, in turn, recruits an E3 ubiquitin ligase from the cytosol to the PROTAC complex, bringing the protein and E3 ligase artificially close, resulting in polyubiquitination of the protein and its subsequent destruction by the proteasome. PROTACs are now in clinical evaluation in a number of cancer indications.

cancer cells

ARV-110 (Arvinas), a PROTAC degrader targeting the androgen receptor, has shown promising results in men with metastatic castration-resistant prostate cancer harbouring mutations which confer resistance to androgen agonist therapy. ARV-471, an oestrogen receptor degrader, is in early clinical evaluation in ER+/HER-2- locally-advanced or metastatic breast cancer.

Exploitation of other promising avenues of attack, such as modifying the tumour microenvironment and targeting DNA repair pathways, is still largely at the translational stage. Progress in understanding and combatting resistance can be expected to accelerate with the growing application of high throughput cancer genomics, cancer proteomics, and metabolomics, allowing genetic and other changes that occur in response to drug treatment to be followed during chemotherapy.

Whole genome sequencing of circulating (cell-free) DNA allows early identification of mutations associated with acquired resistance. CRISPR gene-editing has been applied in the screening of resistance-related genes, to remove resistance through genetic manipulation, and to generate modified models of resistant cells and animals.

About the author

Steven Powell

Steven Powell, president of Ribonexus
Steven has over 20 years’ international experience as CEO in public and private companies, raising over $225M (€214.3M) in equity. In his most recent position as CEO of Belgian biotechnology company eTheRNA Immunotherapies, he helped raise €39M ($41M) in a Series B financing round in 2022. He has extensive board and advisory experience, holding positions in the UK, US, Canada, and several European countries. Steven holds a PhD in microbiology from the University of Aberdeen (Scotland).

About Ribonexus

Ribonexus is an early-stage biotechnology company developing promising new oncology therapies. The company aims to deliver best and first-in-class drugs that restore sensitivity to current targeted therapies in those cancer patients who have become resistant to these treatments. Ribonexus has established a library of small inhibitor molecules, targeting RNA translation. The company’s core intellectual property (IP) was licensed from Pierre Fabre, alongside science foundations from leading French research institutes Gustave Roussy, Institut Curie, and the University of Strasbourg.

Ribonexus was co-founded in 2021 by Adbio partners. In 2021, the company raised €4M in seed funding from AdBio partners, Credit Mutuel Innovation, and Pierre Fabre Invest.


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