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Is resistance to targeted therapy in cancer inevitable?

2021; Cell Press; Volume: 39; Issue: 8 Linguagem: Inglês

10.1016/j.ccell.2021.07.013

1878-3686

Lorey Smith, Karen E. Sheppard, Grant A. McArthur,

Protein Degradation and Inhibitors

Resistance to targeted therapies is a major challenge in cancer care and occurs via genetic and non-genetic mechanisms. In this issue of Cancer Cell, Marin-Bejar et al. demonstrate that melanomas recurrently select genetic or non-genetic resistance trajectories and that targeting neural crest stem cell-like cells prevents non-genetic, but not genetic, resistance. Resistance to targeted therapies is a major challenge in cancer care and occurs via genetic and non-genetic mechanisms. In this issue of Cancer Cell, Marin-Bejar et al. demonstrate that melanomas recurrently select genetic or non-genetic resistance trajectories and that targeting neural crest stem cell-like cells prevents non-genetic, but not genetic, resistance. Targeted anti-cancer therapies have revolutionized cancer care; however, cures remain uncommon due to the development of resistance. Targeted therapies have two major advantages over other anti-cancer therapies: exceptional response rates and low toxicities. Overcoming resistance therefore remains one of the greatest priorities to improve outcomes and quality of life for cancer patients. Remarkable progress has been made in our understanding of the genetic bases of acquired resistance to therapies targeting the mitogen-activated protein kinase (MAPK) pathway in BRAF-mutated melanoma. Significantly, more than 20 mechanisms of genetic resistance have been identified so far (Lim et al., 2017Lim S.Y. Menzies A.M. Rizos H. Mechanisms and strategies to overcome resistance to molecularly targeted therapy for melanoma.Cancer. 2017; 123: 2118-2129Crossref PubMed Scopus (90) Google Scholar). Another reason that targeted therapy fails to provide durable responses is the adaptive nature, or plasticity, of melanoma cells. Continuous exposure to MAPK-targeted therapies can trigger a series of cell-state transitions that allow cells to survive and persist, resulting in minimal residual disease (MRD). These drug-tolerant cells that survive therapy but do not proliferate have been characterized by proliferative to invasive (or mesenchymal) phenotype switching (Kemper et al., 2014Kemper K. de Goeje P.L. Peeper D.S. van Amerongen R. Phenotype switching: tumor cell plasticity as a resistance mechanism and target for therapy.Cancer Res. 2014; 74: 5937-5941Crossref PubMed Scopus (143) Google Scholar), altered mitochondrial metabolism (Haq et al., 2013Haq R. Shoag J. Andreu-Perez P. Yokoyama S. Edelman H. Rowe G.C. Frederick D.T. Hurley A.D. Nellore A. Kung A.L. et al.Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF.Cancer Cell. 2013; 23: 302-315Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar), and adaptive starvation responses (Falletta et al., 2017Falletta P. Sanchez-Del-Campo L. Chauhan J. Effern M. Kenyon A. Kershaw C.J. Siddaway R. Lisle R. Freter R. Daniels M.J. et al.Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma.Genes Dev. 2017; 31: 18-33Crossref PubMed Scopus (138) Google Scholar). These cell-state transitions are thought to allow survival long enough to acquire resistance-conferring mutations; however, accumulating evidence also now suggests they can produce overt resistance in the absence of new genetic events (Hugo et al., 2015Hugo W. Shi H. Sun L. Piva M. Song C. Kong X. Moriceau G. Hong A. Dahlman K.B. Johnson D.B. et al.Non-genomic and immune evolution of melanoma acquiring MAPKi resistance.Cell. 2015; 162: 1271-1285Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar; Rambow et al., 2018Rambow F. Rogiers A. Marin-Bejar O. Aibar S. Femel J. Dewaele M. Karras P. Brown D. Chang Y.H. Debiec-Rychter M. et al.Toward minimal residual disease-directed therapy in melanoma.Cell. 2018; 174: 843-855Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). This type of adaptive, non-genetic resistance to anti-cancer therapies is not unique to melanoma and has emerged as a critical feature of other solid and hematological malignancies (Marine et al., 2020Marine J.C. Dawson S.J. Dawson M.A. Non-genetic mechanisms of therapeutic resistance in cancer.Nat. Rev. Cancer. 2020; 20: 743-756Crossref PubMed Scopus (102) Google Scholar). How prevalent non-genetic resistance is in patients and whether it can be targeted to prevent disease relapse are key questions. The study reported by Marin-Bejar et al. (Marin-Bejar et al., 2021Marin-Bejar O. Rogiers A. Dewaele M. Femel J. Karras P. Pozniak J. Bervoets G. Van Raemdonck N. Pedri D. Swings T. et al.Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma.Cancer Cell. 2021; 56: 1135-1149Abstract Full Text Full Text PDF Scopus (21) Google Scholar) sheds light on these issues by using melanoma patient samples and patient-derived xenograft (PDX) mouse models to probe the frequency and evolution of non-genetic acquired resistance. Previously, using single-cell RNAseq analysis of melanoma PDX mouse models treated with dabrafenib and trametinib (DT), drug-tolerant cells in MRD were cataloged into four transient states: a starved-like melanoma cell (SMC) state, a neural-crest stem cell-like (NCSC) state, an invasive (mesenchymal-like or de-differentiated) state, and a pigmented or hyperdifferentiated state (Rambow et al., 2018Rambow F. Rogiers A. Marin-Bejar O. Aibar S. Femel J. Dewaele M. Karras P. Brown D. Chang Y.H. Debiec-Rychter M. et al.Toward minimal residual disease-directed therapy in melanoma.Cell. 2018; 174: 843-855Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar) (Figure 1). Reconstruction of lineage dynamics between these cellular states indicated that SMC cells emerge prior to the pigmented, invasive, or NCSC cells, consistent with activation of a rapid starvation response followed by the decision to differentiate (pigmented cells) or dedifferentiate (invasive cells or NCSCs). Notably, this cell-state trajectory is consistent with the idea that nutrient deprivation is a major driver of invasive phenotype switching (Falletta et al., 2017Falletta P. Sanchez-Del-Campo L. Chauhan J. Effern M. Kenyon A. Kershaw C.J. Siddaway R. Lisle R. Freter R. Daniels M.J. et al.Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma.Genes Dev. 2017; 31: 18-33Crossref PubMed Scopus (138) Google Scholar). The NCSCs could be identified in clinical biopsies of early-on treatment melanoma patients, and targeting these cells through retinoid X receptor (RXR) inhibition significantly decreased emergence of NCSCs and delayed the onset of resistance (Rambow et al., 2018Rambow F. Rogiers A. Marin-Bejar O. Aibar S. Femel J. Dewaele M. Karras P. Brown D. Chang Y.H. Debiec-Rychter M. et al.Toward minimal residual disease-directed therapy in melanoma.Cell. 2018; 174: 843-855Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). These data provided proof-of-concept that targeting non-genetic mechanisms underpinning drug tolerance may provide new therapeutic avenues to improve patient outcomes. In this current paper, Marin-Bejar et al. (Marin-Bejar et al., 2021Marin-Bejar O. Rogiers A. Dewaele M. Femel J. Karras P. Pozniak J. Bervoets G. Van Raemdonck N. Pedri D. Swings T. et al.Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma.Cancer Cell. 2021; 56: 1135-1149Abstract Full Text Full Text PDF Scopus (21) Google Scholar) further elaborate on the role of NCSCs in non-genetic targeted therapy resistance. First, they establish that genetic mechanisms of DT resistance are absent in ∼26% of melanoma patients based on whole-exome DNA sequencing and that NCSCs are present in ∼38% of patients. By treating a panel of PDX models established from 10 treatment-naive melanoma patients with DT, they show that de novo acquisition of genetic resistance is a common event in melanoma (∼30% of PDXs analyzed). Remarkably, they also show that this evolutionary path is predictable, where the same melanoma will recurrently develop the same genetic resistance over and over again. Intriguingly, the same predictability is also observed for non-genetic adaptive resistance (∼20% of PDXs analyzed). This suggests that some melanomas are prewired to lead to genetic versus non-genetic resistance, raising the exciting possibility that this can be identified in patients and targeted early to disrupt these resistance trajectories. The authors also expand on the mechanisms of DT-induced NCSCs by identifying a focal adhesion kinase (FAK)-dependent autocrine signaling loop, whereby NCSCs produce glial cell line-derived neurotrophic factor (GDNF) that engages GDNF family receptor alpha 2 (GFRA2)-dependent FAK signaling. Inactivation of FAK depletes the reservoir of NCSCs in MRD and delays resistance onset in combination with DT in vivo. However, they observe maximal NCSC depletion and survival benefit only upon co-inhibition of RXR. Finally, while NCSC eradication avoids the non-genetic resistant fate of these melanomas, it does not prevent disease relapse. Resistance still eventually occurs via de novo acquisition of genetic events that remarkably converge upon BRAF amplification (Figure 1). So, does this mean that genetic resistance to targeted therapy is inevitable? Specific details in the study should be kept in mind. Analysis is restricted to primary PDX tumors; however, in most melanoma patients, resistance occurs in metastases, often in multiple organs. Yet detection of NCSCs in patient metastases suggests that primary PDX tumors recapitulate at least some features of residual metastatic disease. The PDX mouse models used across the study are also immunocompromised; therefore it remains unknown whether the immune system influences the predictability of genetic versus non-genetic resistance. In this regard, it is clear that MAPK-targeted therapy elicits diverse immunomodulatory activities such that patient responses are unlikely to result solely from melanoma-intrinsic activities (Hugo et al., 2015Hugo W. Shi H. Sun L. Piva M. Song C. Kong X. Moriceau G. Hong A. Dahlman K.B. Johnson D.B. et al.Non-genomic and immune evolution of melanoma acquiring MAPKi resistance.Cell. 2015; 162: 1271-1285Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar). It would be interesting for future complementary studies to expand these observations by using immunocompetent mouse models with metastatic disease to address how the immune system and tissue-specific microenvironmental factors influence the emergence of distinct drug-tolerant states. Indeed, the authors show that the cellular composition of MRD can predict non-genetic resistance; therefore, understanding how these microenvironmental factors influence MRD composition will likely expand on the far-reaching clinical implications of the findings reported in this study. Another key question is whether other drug-tolerant states play a role in non-genetic resistance. If SMCs are precursors to NCSCs (Rambow et al., 2018Rambow F. Rogiers A. Marin-Bejar O. Aibar S. Femel J. Dewaele M. Karras P. Brown D. Chang Y.H. Debiec-Rychter M. et al.Toward minimal residual disease-directed therapy in melanoma.Cell. 2018; 174: 843-855Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar), can they also be targeted, and would this more effectively ablate drug-tolerant cells and thus prevent disease relapse? This idea is supported by early studies wherein activation of an adaptive starvation response (Falletta et al., 2017Falletta P. Sanchez-Del-Campo L. Chauhan J. Effern M. Kenyon A. Kershaw C.J. Siddaway R. Lisle R. Freter R. Daniels M.J. et al.Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma.Genes Dev. 2017; 31: 18-33Crossref PubMed Scopus (138) Google Scholar) promotes mitochondrial reprogramming to facilitate drug tolerance and limit response to targeted therapies (Haq et al., 2013Haq R. Shoag J. Andreu-Perez P. Yokoyama S. Edelman H. Rowe G.C. Frederick D.T. Hurley A.D. Nellore A. Kung A.L. et al.Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF.Cancer Cell. 2013; 23: 302-315Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar). Targeting mechanisms underpinning this starvation-induced stress response may therefore provide an early avenue to switch drug-tolerant cells from a pro-survival to a pro-death trajectory and thus prevent both acquired genetic and non-genetic resistance. We also note that analysis of pooled extended-survival data from two clinical trials identified long-term survivors following MAPK targeted therapy (overall survival rates of 37% at 4 years, 34% at 5 years) (Robert et al., 2019Robert C. Grob J.J. Stroyakovskiy D. Karaszewska B. Hauschild A. Levchenko E. Chiarion Sileni V. Schachter J. Garbe C. Bondarenko I. et al.Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma.N. Engl. J. Med. 2019; 381: 626-636Crossref PubMed Scopus (507) Google Scholar). This suggests that targeted therapy resistance is not inevitable for all patients. So, what can we learn from these long-term survivors? Whether the composition of MRD in these patients can predict duration of response and what role the immune system and other systemic factors play in these patients are key questions (Figure 1). However, access to tissue biopsies in these patients is often problematic. Future development of liquid biopsies, imaging strategies, or cellular analyses following a neoadjuvant approach capable of detecting MRD composition will likely be transforming and will build on the observations reported in this current study. Continuing to dissect the biology of MRD may therefore allow us to prevent the emergence of resistance and increase cures with targeted therapies. Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanomaMarin-Bejar et al.Cancer CellJune 17, 2021In BriefMarin-Bejar et al. identify focal adhesion kinase (FAK) as a vulnerability of melanoma drug persisters harboring a neural crest-like state. Targeting these cells, using a FAK inhibitor, prevents the development of nongenetic, but not genetic, resistance, indicating that the path to resistance is dictated by the cellular composition of minimal residual disease. Full-Text PDF