Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma

Dharanipragada, Prashanthi; Zhang, Xiao; Liu, Sixue; Lomeli, Shirley H.; Hong, Aayoung; Wang, Yan; Yang, Zhentao; Lo, Kara Z.; Vega-Crespo, Agustin; Ribas, Antoni; Moschos, Stergios J.; Moriceau, Gatien; Lo, Roger S.

doi:10.1158/2159-8290.cd-22-0787

Cited by 41 publications

(21 citation statements)

References 69 publications

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“…If the FA pathway cannot be directly targeted even in short treatment intervals, targeting upstream kinases also offers promise. Clinical ATR, ATM, and DNA-PK inhibitors already exist for a variety of indications, and our work suggests that this class of kinases is at play in helping many types of MAPK-mutant escapee cells adapt and evolve amid cell-cycle stress and DNA damage, paralleling recent studies noting the effective cotreatment of MAPK inhibition with ATM inhibitors ( 76 ) or with DNA-PK inhibitors ( 77 ).…”

Section: Discussionsupporting

confidence: 64%

Multiple cancers escape from multiple MAPK pathway inhibitors and use DNA replication stress signaling to tolerate aberrant cell cycles

Hoffman,

Nangia,

Ill

et al. 2023

Sci. Signal.

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Many cancers harbor pro-proliferative mutations of the mitogen-activated protein kinase (MAPK) pathway. In BRAF-driven melanoma cells treated with BRAF inhibitors, subpopulations of cells escape drug-induced quiescence through a nongenetic manner of adaptation and resume slow proliferation. Here, we found that this phenomenon is common to many cancer types driven by EGFR, KRAS, or BRAF mutations in response to multiple, clinically approved MAPK pathway inhibitors. In 2D cultures and 3D spheroid models of various cancer cell lines, a subset of cells escaped drug-induced quiescence within 4 days to resume proliferation. These “escapee” cells exhibited DNA replication deficits, accumulated DNA lesions, and mounted a stress response that depended on the ataxia telangiectasia and RAD3-related (ATR) kinase. We further identified that components of the Fanconi anemia (FA) DNA repair pathway are recruited to sites of mitotic DNA synthesis (MiDAS) in escapee cells, enabling successful completion of cell division. Analysis of patient tumor samples and clinical data correlated disease progression with an increase in DNA replication stress response factors. Our findings suggest that many MAPK pathway–mutant cancers rapidly escape drug action and that suppressing early stress tolerance pathways may achieve more durable clinical responses to MAPK pathway inhibitors.

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Section: Discussionsupporting

confidence: 64%

Multiple cancers escape from multiple MAPK pathway inhibitors and use DNA replication stress signaling to tolerate aberrant cell cycles

Hoffman,

Nangia,

Ill

et al. 2023

Sci. Signal.

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“…Increased DSB persistence likely promotes ecDNA formation by (i) increasing the temporal overlap of the DSBs; (ii) enabling dissociation of the DSB ends from the their legitimate partners; and (iii) with increasing time, favoring the intramolecular ligation event ( Fig 4F ). Recent work has suggested that DNA-PKcs inhibition can decrease formation of ecDNA by chromothripsis, or decrease the genomic span of these ecDNAs (9,31). These seemingly diametric results may be a consequence of a greater reliance on NHEJ to ligate fragments generated by chromothripsis (32).…”

Section: Discussionmentioning

confidence: 99%

Disparate pathways for extrachromosomal DNA biogenesis and genomic DNA repair

Rose,

Wong,

Daniel

et al. 2023

Preprint

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Oncogene amplification on extrachromosomal DNA (ecDNA) is a pervasive driver event in cancer, yet our understanding of how ecDNA forms is limited. Here, we couple a CRISPR-based method for induction of ecDNA with extensive characterization of newly formed ecDNA to examine ecDNA biogenesis. We find that DNA circularization is efficient, irrespective of 3D genome context, with formation of a 1 Mb and 1.8 Mb ecDNA both reaching 15%. We show non-homologous end joining and microhomology mediated end joining both contribute to ecDNA formation, while inhibition of DNA-PKcs and ATM have opposing impacts on ecDNA formation. EcDNA and the corresponding chromosomal excision scar form at significantly different rates and respond differently to DNA-PKcs and ATM inhibition. Taken together, our results support a model of ecDNA formation in which double strand break ends dissociate from their legitimate ligation partners prior to joining of illegitimate ends to form the ecDNA and excision scar.

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“…Although primary resistance is mainly linked to the initial tumor cell status and their microenvironment, to date there is still no biomarker to identify patients with BRAF V600 -mutated melanoma who will not respond to MAPKi. Acquired resistance involves the adaptation of tumor cells through genetic or non-genetic mechanisms [37, 38]. A single-cell study showed that tumor heterogeneity and melanoma cell plasticity influence tumor behavior and evolution under MAPKi pressure [39].…”

Section: Discussionmentioning

confidence: 99%

Improved prediction of the response duration to MAPK inhibitors in patients with advanced melanoma using baseline genomic data and machine learning algorithms

Dandou,

Amin,

D’Hondt

et al. 2023

Preprint

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PurposeBaseline genomic data have not demonstrated significant value for predicting the response to MAPK inhibitors (MAPKi) in patients with BRAFV600-mutated melanoma. We used machine learning algorithms and pre-processed genomic data to test whether they could contain useful information to improve the progression-free survival (PFS) prediction.Experimental designThis exploratory analysis compared the predictive performance of a dataset that contained clinical features alone and supplemented with baseline genomic data. Whole and partial exon sequencing data from four cohorts of patients with BRAFV600-mutated melanoma treated with MAPKi were used: two cohorts as training/evaluation set (n = 111) and two as validation set (n = 73). Genomic data were pre-processed using three strategies to generate eight different genomic datasets. Several machine learning algorithms and one statistical algorithm were employed to predict PFS. The performance of these survival models was assessed using the concordance index, time-dependent receiver operating characteristic (ROC) curve and Brier score.ResultsThe cross-validated model performance improved when pre-processed genomic data, such as mutation rates, were added to the clinical features. In the validation dataset, the best model with genomic data outperformed the best model with clinical features alone. The trend towards improved prediction with baseline genomic data was maintained when data were censored according to the two clinical setting scenarios (duration of clinical benefit and progression before 12 months).ConclusionIn our models, baseline genomic data improved the prediction of response duration and could be incorporated into the development of predictive models of response pattern to MAPKi in melanoma.Translational RelevanceCurrently, biomarkers are lacking to robustly predict the response to therapy targeting the MAPK pathway in advanced melanoma. Therefore, in the clinic, a trial-and-error approach is often used. Baseline genomic mutation profiles represent a comparably stable biological readout that is easily accessible and measurable in clinical routine. Therefore, they might represent candidate predictive biomarker signatures. However, previous studies could not show a clear predictive signal for the response to MAPK inhibitors (MAPKi) in patients with BRAFV600-mutated melanoma. Here, our exploratory machine learning-based analysis highlighted an improved prediction of progression-free survival when clinical and genomic data were combined, even when using only partial exome sequencing data. This suggests that baseline genomic data could be incorporated in the development of predictive models of the response to MAPKi in advanced melanoma by leveraging the results of current routine partial exome sequencing.Interest statementThe authors declare no potential conflicts of interest.

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Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma

Cited by 41 publications

References 69 publications

Multiple cancers escape from multiple MAPK pathway inhibitors and use DNA replication stress signaling to tolerate aberrant cell cycles

Multiple cancers escape from multiple MAPK pathway inhibitors and use DNA replication stress signaling to tolerate aberrant cell cycles

Disparate pathways for extrachromosomal DNA biogenesis and genomic DNA repair

Improved prediction of the response duration to MAPK inhibitors in patients with advanced melanoma using baseline genomic data and machine learning algorithms

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