Drug resistance is perhaps the greatest challenge in improving outcomes for cancer patients undergoing treatment with targeted therapies. It is becoming clear that “persisters,” a subpopulation of ...drug-tolerant cells found in cancer populations, play a critical role in the development of drug resistance. Persisters are able to maintain viability under therapy but are typically slow cycling or dormant. These cells do not harbor classic drug resistance driver alterations, and their partial resistance phenotype is transient and reversible upon removal of the drug. In the clinic, the persister state most closely corresponds to minimal residual disease from which relapse can occur if treatment is discontinued or if acquired drug resistance develops in response to continuous therapy. Thus, eliminating persister cells will be crucial to improve outcomes for cancer patients. Using lung cancer targeted therapies as a primary paradigm, this review will give an overview of the characteristics of drug-tolerant persister cells, mechanisms associated with drug tolerance, and potential therapeutic opportunities to target this persister cell population in tumors.
Targeted therapies have changed the landscape of treatments for non-small cell lung cancer (NSCLC). Specific targeted therapies have been approved for NSCLC patients harboring genetic alterations in ...four oncogenes, and agents targeting additional oncogenic drivers are under investigation. Standard first-line chemotherapy has been supplanted by these targeted therapies due to superior efficacy and lower toxicity. Despite excellent response rates and durable responses in some cases, most patients experience relapse within a few years due to the development of acquired drug resistance. Next generation targeted therapies are being developed to overcome drug resistance and extend the duration of therapy. In this review, we summarize the current treatment strategies for the major targetable oncogenic mutations/alterations in NSCLC and discuss the mechanisms leading to acquired drug resistance.
APOBEC3 cytidine deaminases have emerged as key drivers of mutagenesis in a wide spectrum of tumor types and are now appreciated to play a causal role in driving tumor evolution and drug resistance. ...As efforts to develop APOBEC3 inhibitors progress, understanding the timing and consequences of APOBEC3-mediated mutagenesis in distinct clinical contexts will be critical for guiding the development of anti-cancer therapeutic strategies.
While significant advancements have been made in the available therapies for metastatic non-small cell lung cancer (NSCLC), acquired resistance remains a major barrier to treatment. We have not yet ...achieved the ability to cure advanced NSCLC with systemic therapy, despite our growing understanding of many of the oncogenic drivers of this disease. Rather, the emergence of drug-tolerant and drug-resistant cells remains the rule, even in the face of increasingly potent targeted therapies. In this review, we provide a broad overview of the mechanisms of resistance to targeted therapy that have been demonstrated across molecular subtypes of NSCLC, highlighting the dynamic interplay between driver oncogene, bypass signaling pathways, shifting cellular phenotypes, and surrounding tumor microenvironment.
Abstract
Mutant-selective KRASG12C inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in KRASG12C-mutant cancers, including non–small cell lung cancer ...(NSCLC). However, mechanisms underlying clinical acquired resistance to KRASG12C inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a patient with KRASG12C NSCLC who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (KRAS, NRAS, BRAF, MAP2K1), all of which converge to reactivate RAS–MAPK signaling. Notably, a novel KRASY96D mutation affecting the switch-II pocket, to which MRTX849 and other inactive-state inhibitors bind, was identified that interferes with key protein–drug interactions and confers resistance to these inhibitors in engineered and patient-derived KRASG12C cancer models. Interestingly, a novel, functionally distinct tricomplex KRASG12C active-state inhibitor RM-018 retained the ability to bind and inhibit KRASG12C/Y96D and could overcome resistance.
Significance:
In one of the first reports of clinical acquired resistance to KRASG12C inhibitors, our data suggest polyclonal RAS–MAPK reactivation as a central resistance mechanism. We also identify a novel KRAS switch-II pocket mutation that impairs binding and drives resistance to inactive-state inhibitors but is surmountable by a functionally distinct KRASG12C inhibitor.
See related commentary by Pinnelli and Trusolino, p. 1874.
This article is highlighted in the In This Issue feature, p. 1861
Matched pre-/posttreatment tissue biopsies from patients with
-mutant non-small cell lung cancer demonstrate that histologic transformations, including both small-cell carcinoma and squamous ...transformation, are unexpectedly common among patients progressing on first-line osimertinib. The study highlights the key role of tissue testing and underscores the need for innovative therapeutic approaches to prevent, rather than treat, resistance.
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Prostaglandins are lipid-derived autacoids that modulate many physiological systems including the CNS, cardiovascular, gastrointestinal, genitourinary, endocrine, respiratory, and immune systems. In ...addition, prostaglandins have been implicated in a broad array of diseases including cancer, inflammation, cardiovascular disease, and hypertension. Prostaglandins exert their effects by activating rhodopsin-like seven transmembrane spanning G protein-coupled receptors (GPCRs). The prostanoid receptor subfamily is comprised of eight members (DP, EP1-4, FP, IP, and TP), and recently, a ninth prostaglandin receptor was identified-the chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2). The precise roles prostaglandin receptors play in physiologic and pathologic settings are determined by multiple factors including cellular context, receptor expression profile, ligand affinity, and differential coupling to signal transduction pathways. This complexity is highlighted by the diverse and often opposing effects of prostaglandins within the immune system. In certain settings, prostaglandins function as pro-inflammatory mediators, but in others, they appear to have anti-inflammatory properties. In this review, we will discuss the pharmacology and signaling of the nine known prostaglandin GPCRs and highlight the specific roles that these receptors play in inflammation and immune modulation.
Evolved resistance to tyrosine kinase inhibitor (TKI)-targeted therapies remains a major clinical challenge. In epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC), ...failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug-tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs. While therapeutic approaches targeting fully resistant cells, such as those harboring an EGFR
mutation, have been developed, a clinical strategy for preventing the emergence of persister cells remains elusive. Using mesenchymal cell lines derived from biopsies of patients who progressed on EGFR TKI as surrogates for persister populations, we performed whole-genome CRISPR screening and identified fibroblast growth factor receptor 1 (FGFR1) as the top target promoting survival of mesenchymal EGFR mutant cancers. Although numerous previous reports of FGFR signaling contributing to EGFR TKI resistance in vitro exist, the data have not yet been sufficiently compelling to instigate a clinical trial testing this hypothesis, nor has the role of FGFR in promoting the survival of persister cells been elucidated. In this study, we find that combining EGFR and FGFR inhibitors inhibited the survival and expansion of EGFR mutant drug-tolerant cells over long time periods, preventing the development of fully resistant cancers in multiple vitro models and in vivo. These results suggest that dual EGFR and FGFR blockade may be a promising clinical strategy for both preventing and overcoming EMT-associated acquired drug resistance and provide motivation for the clinical study of combined EGFR and FGFR inhibition in EGFR-mutated NSCLCs.
Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes ...in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Results The most frequent ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). We analyzed 77 tumor biopsy specimens from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 0%; P < .001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R ( P = .010 and .015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 0.79; P = .011). Conclusion Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.
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