scholarly journals Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Zuan-Fu Lim ◽  
Patrick C. Ma
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Minimal Residual Disease ◽  
Tumor Heterogeneity ◽  
Residual Disease ◽  
Resistance Mechanisms ◽  
Intratumoral Heterogeneity ◽  
Acquired Drug Resistance ◽  
Minimal Residual

AbstractThe biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells’ ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity—the driving force behind minimal residual disease—is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.

scholarly journals MA17.07 Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer

2017 ◽  
Vol 12 (1) ◽  
pp. S445
Author(s):  
Aadel Chaudhuri ◽  
Alexander Lovejoy ◽  
Jacob Chabon ◽  
Aaron Newman ◽  
Henning Stehr ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Tumor Dna ◽  
Minimal Residual

Targeting lethal minimal residual disease in small cell lung cancer

2003 ◽  
Vol 30 (1) ◽  
pp. 79-85 ◽  
Author(s):  
Jyoti D. Patel ◽  
Lee M. Krug ◽  
Christopher G. Azzoli ◽  
Jorge Gomez ◽  
Mark G. Kris ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Minimal Residual Disease ◽  
Cell Lung Cancer ◽  
Residual Disease ◽  
Small Cell ◽  
Small Cell Lung ◽  
Minimal Residual

scholarly journals Enhanced cohesion promotes chromosome stability and limits acquired drug resistance in non small cell lung cancer

2020 ◽  
Author(s):  
Nicole M Hermance ◽  
Elizabeth A Crowley ◽  
Conor P Herlihy ◽  
Amity L Manning
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Heterogeneity ◽  
Small Cell ◽  
Tumor Evolution ◽  
Small Cell Lung ◽  
Acquired Drug Resistance

AbstractChromosome instability, or CIN, defined as a high frequency of whole chromosome gains and losses, is prevalent in many solid tumors. CIN has been shown to promote intra-tumor heterogeneity and correspond with tumor aggressiveness, drug resistance and tumor relapse. However, whether CIN promotes the acquisition of genomic changes responsible for drug resistance remain unclear. Here we assess the role of CIN in the acquisition of drug resistance in non small cell lung cancer. We show that impairment of centromeric cohesion underlies the generation of whole chromosome segregation errors and CIN in non small cell lung cancer cells. Further, we demonstrate that centromere-specific enhancement of chromosome cohesion strongly suppresses CIN and reduces intra-tumor heterogeneity. We demonstrate that suppression of CIN has no impact on NSCLC cell proliferation in vitro nor in tumor initiation in mouse xenograft models. However, suppression of CIN alters the timing and molecular mechanism that drive acquired drug resistance. These findings suggest mechanisms to suppress CIN may serve as effective co-therapies to limit tumor evolution and sustain drug response.

scholarly journals APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

2021 ◽  
Author(s):  
Hideko Isozaki ◽  
Ammal Abbasi ◽  
Naveed Nikpour ◽  
Adam Langenbucher ◽  
Wenjia Su ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Targeted Therapies ◽  
Acquired Resistance ◽  
Small Cell ◽  
Tumor Evolution ◽  
Small Cell Lung ◽  
Acquired Drug Resistance

AbstractAcquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1‒6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

Leveraging phased variants for personalized minimal residual disease detection in localized non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8518-8518
Author(s):  
David Matthew Kurtz ◽  
Jacob J. Chabon ◽  
Brian Sworder ◽  
Lyron Co Ting Keh ◽  
Joanne Soo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
High Specificity ◽  
Disease Recurrence ◽  
Circulating Tumor Dna ◽  
Error Rates ◽  
Background Error ◽  
Background Rate ◽  
Minimal Residual

8518 Background: Detection of circulating tumor DNA (ctDNA) has prognostic value in lung cancer and could facilitate minimal residual disease (MRD) driven approaches. However, the sensitivity of ctDNA detection is suboptimal due to the background error rates of existing assays. We developed a novel method leveraging multiple mutations on a single cell-free DNA molecule (“phased variants” or PVs) resulting in an ultra-low error profile. Here we develop and apply this approach to improve MRD in localized NSCLC. Methods: To identify the prevalence of PVs, we reanalyzed whole genome sequencing (WGS) from 2,538 tumors and 24 cancer types from the pan-cancer analysis of whole genomes (PCAWG). We applied Phased Variant Enrichment and Detection Sequencing (PhasED-Seq) to track personalized PVs in localized NSCLC. We compared PhasED-Seq to a single nucleotide variant (SNV)-based ctDNA method. Results: In the PCAWG dataset, we found that PVs were common in both lung squamous cell carcinomas (LUSC, median 1,268/tumor; rank 2nd) and adenocarcinomas (LUAD, median 655.5/tumor; rank 3rd). However, PVs did not occur in stereotyped genomic regions. Thus, to leverage PhasED-Seq, we performed tumor/normal WGS to identify PVs, followed by design of personalized panels targeting PVs to allow deep cfDNA sequencing. We performed personalized PhasED-Seq for 5 patients with localized NSCLC. PVs were identified from WGS of tumor FFPE and validated by targeted resequencing in all cases (median 248/case). The background rate of PVs was lower than that of SNVs, even when considering duplex molecules (background: SNVs, 3.8e-5; duplex SNVs, 1.0e-5; PVs, 1.2e-6; P < 0.0001). We next assessed PhasED-Seq for MRD detection in 14 patient plasma samples. Both SNVs and PhasED-Seq had high specificity in healthy control cfDNA (95% and 97% respectively). Using SNVs, ctDNA was detected in 5/14 samples; PhasED-Seq detected all of these with nearly identical tumor fractions (Spearman rho = 0.97). However, PhasED-Seq also detected MRD in an additional 5 samples containing tumor fractions as low as 0.000094% (median 0.0004%). We analyzed serial samples from a patient with stage III LUAD treated with chemoradiotherapy (CRT) and durvalumab. SNV-based ctDNA and PhasED-Seq detected similar MRD levels (0.8%) prior to therapy. However, 3 samples collected during CRT, as well as before and during immunotherapy, were undetectable by SNVs. SNV-based ctDNA then re-emerged at disease recurrence. PhasED-Seq detected MRD in all 3 samples not detected by SNVs with tumor fractions as low as 0.00016%, including prior to immunotherapy (8 months prior to progression). Similar improvements were seen in samples not detected by SNVs from 2 additional patients. Conclusions: Personalized ctDNA monitoring via PVs is feasible and improves MRD detection in localized NSCLC. PhasED-Seq allows clinical studies testing personalized treatment based on MRD.

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