Cancer Evolution and the Limits of Predictability in Precision Cancer Medicine

Lipiński, Kamil; Barber, Louise J.; Davies, Matthew N.; Ashenden, Matthew; Sottoriva, Andrea; Gerlinger, Marco

doi:10.1016/j.trecan.2015.11.003

Cited by 241 publications

(203 citation statements)

References 106 publications

(154 reference statements)

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“…Heterogeneity of resistance mechanisms is consistent with a clonal adaptation that occurred in the course of an evolutionary process. Subclonal heterogeneity allows dynamic tumor adaption and is generally a key cause of treatment failure (56). To our knowledge, no therapy is available to counteract TP53 mutations or expression of ΔNTP63 and ΔNTP73; currently, only MDM4 (48) and BCL-xL (49,50) can be targeted pharmacologically.…”

Section: Discussionmentioning

confidence: 99%

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Chapeau

Gembarska

Durand

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf −/− mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposonmediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy.drug resistance | MDM2 inhibitor | piggyBac screen | cancer A mong the genes most commonly altered in human cancer, regardless of tumor type, are tumor protein 53 (TP53) tumor suppressor (1) and CDKN2A (INK4a/ARF) (2). The latter gene encodes two tumor suppressor proteins: p16INK4a (3), an inhibitor of cyclin D-dependent kinases that, at least in part, regulates the function of the retinoblastoma protein (RB), and p19ARF (4), a negative regulator of double minute 2 protein (MDM2) function that activates TP53, thereby inducing cell cycle arrest or apoptosis. TP53 protein levels are regulated through MDM2-mediated degradation.Toward the goal of reactivating TP53 in cells harboring inactivating upstream pathway alterations, compounds inhibiting the interaction between MDM2 and TP53, preventing TP53 degradation, have been discovered. Such agents induce TP53 reactivation in tumors in which the TP53 gene is wild type (5-8).Although preclinical studies of such MDM2 inhibitors have demonstrated significant antitumor activity, tumors commonly relapse (9, 10).Rapid emergence of resistance is...

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Section: Discussionmentioning

confidence: 99%

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Chapeau

Gembarska

Durand

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Relatedly, the fact that cancer genes can harbor a statistically significant enrichment of subclonal mutations suggests a signal of selection can be present throughout tumor evolution (McGranahan et al, 2015). It remains an open question whether distinct clinical behaviors can be observed depending on the mode of tumor evolution, or whether the occurrence of neutral evolution and drift may limit the ability to predict a tumor's next step (Lipinski et al, 2016).…”

Section: Processes Of Cancer Genome Evolution and Evolutionary Debatesmentioning

confidence: 99%

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

McGranahan

Swanton

2017

Cell

2,111

1,694

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Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here we review data and technologies that have revealed intra-tumor heterogeneity across cancer types, and the dynamics, constraints and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis, and consider the role of the tumor microenvironment in engendering heterogeneity and drug-resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immunemicroenvironment whilst limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome.

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“…Moreover, every tumor is unique, even when only genetic alterations are considered (133), and stochastic events might constitute an intrinsic barrier to the prediction of specific mechanisms of drug resistance (134). The clinical implementation of liquid biopsies could provide real-time assessment of tumor evolution, thus allowing a physician to undertake appropriate therapeutic measures and choose the best strategy to harness the evolution of a patient's tumor.…”

Section: Leveraging Biomarkers and Real-time Assessment Of Tumor Evolmentioning

confidence: 99%

Tumor Evolution as a Therapeutic Target

Amirouchene-Angelozzi

2017

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Recent technological advances in the fi eld of molecular diagnostics (including blood-based tumor genotyping) allow the measurement of clonal evolution in patients with cancer, thus adding a new dimension to precision medicine: time. The translation of this new knowledge into clinical benefi t implies rethinking therapeutic strategies. In essence, it means considering as a target not only individual oncogenes but also the evolving nature of human tumors. Here, we analyze the limitations of targeted therapies and propose approaches for treatment within an evolutionary framework.Signifi cance: Precision cancer medicine relies on the possibility to match, in daily medical practice, detailed genomic profi les of a patient's disease with a portfolio of drugs targeted against tumor-specifi c alterations. Clinical blockade of oncogenes is effective but only transiently; an approach to monitor clonal evolution in patients and develop therapies that also evolve over time may result in improved therapeutic control and survival outcomes. Cancer Discov; 7(8);

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Cancer Evolution and the Limits of Predictability in Precision Cancer Medicine

Cited by 241 publications

References 106 publications

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

Tumor Evolution as a Therapeutic Target

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Cancer Evolution and the Limits of Predictability in Precision Cancer Medicine

Cited by 241 publications

References 106 publications

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

Tumor Evolution as a Therapeutic Target

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Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model