Tackling therapy resistance in cancer
Authors: Jerry C. Madukwe
Journal: Trends in Pharmacological Sciences (2024)

In recent years, novel drugs including small molecule drugs and biologics for the treatment of different types of cancers such as lung and colorectal cancer, which pose significant health and economic burden, have been approved by the FDA. However, resistance to these drugs is common and affects disease prognosis and quality of life of patients. Towards eradication of therapy resistance, clinicians and research scientists in different parts of the world have leveraged advanced, new technological tools to gain greater insights into the molecular underpinnings of cancer progression and resistance to treatment. These insights promise to revolutionize current approaches in tackling therapy resistance in cancer. This special issue of Trends in Pharmacological Sciences (TIPS) presents expert perspectives of clinicians and research scientists from around the world on the recent developments in the cancer drug resistance field [1.Nussinov, R. et al. Directions to overcome therapy resistance in cancer. Trends Pharmacol. Sci., this issueGoogle Scholar] and exciting future avenues of research to tackle therapy resistance in cancer. Genomic alterations in ErbB receptors on the cell surface are frequently observed in multiple cancers. ErbB receptor signaling is involved in the regulation of cell growth, differentiation, and proliferation. Excessive ErbB receptor signaling due to activation mutations are drivers of cancer progression and resistance. The efficacy of current anti-ErbB cancer treatments, including small molecule inhibitors targeting ErbB receptor tyrosine kinase and monoclonal antibodies (mAb) targeting ErbB receptors, are limited due to drug-resistant mutations and crosstalk activations that pre-exist or emerge following treatment. Van Seuningen and colleagues [2.Stoup N. et al.Emerging paradigms and recent progress in targeting ErbB in cancers.Trends Pharmacol. Sci. 2024; (this issue)Google Scholar] provide an overview of current FDA-approved drugs targeting ErbB receptors, as well as evaluate mechanisms of resistance and recent innovative strategies designed to overcome resistance. They also highlight the importance of the ErbB interactome as an under-explored avenue for the discovery of novel anti-ErbB therapeutics to optimize cancer treatment. Immunotherapy is a type of cancer treatment that triggers one's immune system to fight the cancer. Advances in our understanding of tumor immunity and the microenvironment led to the development of immunotherapies including immune checkpoint inhibitors (ICIs) to target proteins on the surface of tumor cells which dampen anti-tumor immune responses, such as PD-L1/PD-1 and CTLA-4. These immunotherapies have been approved in multiple clinical settings, but efficacy has been limited due to vast and heterogeneous primary and adaptive resistance mechanisms. Focusing on lung cancer, which is the leading cause of cancer-related deaths, in a Review, Gibbons and colleagues [3.Konen J.M. et al.Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities.Trends Pharmacol. Sci. 2024; (this issue)Abstract Full Text Full Text PDF Scopus (0) Google Scholar] discuss emerging tumor intrinsic and extrinsic mechanisms of immunotherapy resistance, with many of these identified by recent advances in sequencing and spatial technologies. They also highlight novel therapeutic strategies to combat these resistance mechanisms and discuss current challenges and impending opportunities for improving ICI efficacy. Inside cancer cells, transcription factors and epigenetics modulators are important targets for tackling resistance in cancers due to their roles in overexpression of cancer activators or underexpression of repressors. It is well known that the MYC family of proteins, transcription factors that activate expression of many pro-proliferative genes and play a major role in the resistance mechanisms and pathology of cancers, is hard to drug directly. Recent progress in identifying idealized combinations of drugs and dual targeting drugs that can at once synergize in their antitumor effect, lowering effective doses and side-effect potential, is promising. In a Review, Thompson and Shortt [4.Thompson P.E. Shortt J. Defeating MYC with drug combinations or dual-targeting drugs.Trends Pharmacol. Sci. 2024; (this issue)Google Scholar] discuss relevant individual pharmacological targets that have been pursued to block MYC functions and recently identified combination targeted treatments where both targets are relevant to MYC function. They also examine the potential of extending identified target pairs into dual targeting drugs. Beyond MYC but still focused on improving drug combination efficacy, in another Review, Nussinov and colleagues [5.Nussinov, R. et al. Anticancer drugs: how to select small molecule combinations. Trends Pharmacol. Sci., this issueGoogle Scholar] emphasize why drug combinations are essential for tackling various cancers and therapy resistance. Informed by recent developments in the field, they also outline possible types of drug combinations, including same protein combinations, same pathway combinations, combinations of different types of alternative or compensatory pathways, and combinations targeting over or under expression that may lead to better therapeutic outcomes. Although the idea that increased understanding of drug resistance mutations and alternative pathways activated in resistant cells holds great potential for optimizing cancer drug combinations is well accepted, it is becoming recognized that pathways and mutations that promote cancer stemness and modify cell metabolism may be more sensitive to therapy combinations that target them. Two articles discuss emerging targets in cancer that may be explored further for therapeutic benefits. First, Zhavoronkov and colleagues [6.Ewald, C.Y. et al. TNIK's emerging role in cancer, metabolism and age-related diseases. Trends Pharmacol. Sci., this issueGoogle Scholar] review recent discoveries that implicate Traf2- and Nck-interacting kinase (TNIK) in treatment resistance and cancer stemness and evaluate newly developed TNIK inhibitors that may be combined with ICIs to synergize cancer cell death. Second, Terry and Hay [7.Terry A.R. Hay N. Emerging targets in lipid metabolism for cancer therapy.Trends Pharmacol. Sci. 2024; (this issue)Abstract Full Text Full Text PDF Google Scholar] provide a comprehensive overview of emerging lipid metabolic targets related to fatty acid synthesis, fatty acid uptake, and lipid desaturation in cancer cells. They also discuss how lipids impact tumor progression and tumor-infiltrating immune cells, lipid inhibitors in clinical trials for cancer therapy, and opportunities to enhance ICI treatment when combined with lipid metabolism inhibitors. The articles contained in this issue are only some of the latest cutting-edge developments in the cancer drug resistance field. I thank all authors and referees for working within very tight deadlines for this issue. My apologies to the many scientists whose work in the field we were unable to add to this collection due to space and time limitations. I hope that our readers enjoy the articles and come away excited and inspired by the exciting developments in the cancer drug resistance field. I welcome any comments and ideas at [email protected].