Dysregulated Signalling Pathways Driving Anticancer Drug Resistance

Abstract

One of the leading causes of death worldwide, in both men and women, is cancer. Despite the significant development in therapeutic strategies, the inevitable emergence of drug resistance limits the success and impedes the curative outcome. Intrinsic and acquired resistance are common mechanisms responsible for cancer relapse. Several factors crucially regulate tumourigenesis and resistance, including physical barriers, tumour microenvironment (TME), heterogeneity, genetic and epigenetic alterations, the immune system, tumour burden, growth kinetics and undruggable targets. Moreover, transforming growth factor-beta (TGF-β), Notch, epidermal growth factor receptor (EGFR), integrin-extracellular matrix (ECM), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), wingless-related integration site (Wnt/β-catenin), Janus kinase/signal transducers and activators of transcription (JAK/STAT) and RAS/RAF/mitogen-activated protein kinase (MAPK) signalling pathways are some of the key players that have a pivotal role in drug resistance mechanisms. To guide future cancer treatments and improve results, a deeper comprehension of drug resistance pathways is necessary. This review covers both intrinsic and acquired resistance and gives a comprehensive overview of recent research on mechanisms that enable cancer cells to bypass barriers put up by treatments, and, like "satellite navigation", find alternative routes by which to carry on their "journey" to cancer progression.

Keywords: JAK/STAT pathway; PI3K/Akt/mTOR pathway; RAS/RAF/MAPK/ERK signalling; Wnt/β-catenin pathway; cancer; drug resistance; signalling pathways; tumourigenesis.

Figure 1

Stages of carcinogenesis. Exposure to a carcinogenic agent, such as viruses, chemicals or radiation, will induce DNA damage in one or a small population of healthy cells. Failure in DNA repair will lead to intrinsic or acquired mutations that will potentially affect the cell’s biological process, such as its growth and apoptosis, resulting in initiating premalignancy transformation. The transformed cells will then promote the growth of neoplastic lesions, which hold so many genetic alterations. Chemopreventive agents, such as natural agents derived from dietary sources (e.g., curcumin, resveratrol) or bioactive molecules (tamoxifen, raloxifene), will be used to block and suppress cell growth rates at those stages to reverse or delay the carcinogenesis process. Failure to eliminate those premalignant cells will lead to the progression stage, resulting in the formation of a malignant tumour. Chemopreventive agents will be given at this stage to inhibit cell invasion, metastasis and angiogenesis. Failure to do so will result in metastasis via the bloodstream or lymphatic system. Created with BioRender.com.

Figure 2

Potential mechanisms in cancer drug resistance. Several mechanisms trigger drug resistance in cancer. Exposure of cancer cells to therapeutic pressure induces genomic alterations and mutations, either (1) intrinsic, represented in red, or (2) acquired, represented in green, after cycles of treatment, which in both cases result in drug resistance. (3) Slow-growing tumours and (4) intractable genomic drivers (e.g., MYC and TP53) play a critical role in the emergence of drug resistance. All these factors play a vital role in tumour heterogeneity leading to genetic diversity. (5) Tumour microenvironments mediate resistance by several mechanisms, e.g., (a) escaping immune surveillance, (b) stimulating paracrine growth factors by tumour-associated cells to promote cancer cell growth and (c) the neovascularization of tumour cells by overexpressing vascular endothelial growth factor receptors (VEGFR). All these factors make a complex network that triggers drug resistance in cancer. Created with BioRender.com.

Figure 3

Drug resistance management. Strategies used to manage and overcome drug resistance are depicted in this picture. (1) Earlier detection of actionable genomic modifications using ctDNA is a powerful tool to predict cancer recurrence influencing more effective treatment decision-making that results in a better response to treatment. (2 and 3) Immunotherapy, such as checkpoint inhibitors, can be used as monotherapy or in combination to simultaneously target multiple pathways and increase treatment effectiveness. (4) Mapping cancer dependencies using DeepMap is an effective approach to predicting genes responsible for drug resistance and identifying new genetic targets, thereby facilitating the discovery of drugs that can potentially overcome resistance. Created with BioRender.com.

Figure 4

Targeting multiple pathways in drug-resistant cells. The impact of many therapies on signalling in drug-resistant cells is depicted in this picture. (A) When targeting a single signalling pathway, such as PGFR signalling, cancer cells become resistant to PDGFR inhibitors (such as CHMFL-PDGFR-159) by activating compensatory signalling pathways of alternative RTKs (e.g., FGFR or VEGFR) leading to cell survival and migration. (B) However, resistance and signalling reactivation can be overcome by combination therapy and multi-target kinase inhibitors that target multiple signalling pathways leading to effective inhibition of cancer progression and drug resistance. Created with BioRender.com.