- Email: [email protected]
MEK Inhibition
Cancer Cell
Previews Senesce to Survive: YAP-Mediated Dormancy Escapes EGFR/MEK Inhibition Igor Bado1,2,3 and Xiang H.-F. Zhang1,2,3,4,* 1Lester
and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA 3Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA 4McNair Medical Institute, Baylor College of Medicine, BCM600, One Baylor Plaza, Houston, TX 77030, USA *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2019.12.008 2Dan
Therapeutic resistance is a major challenge in cancer treatment. In this issue of Cancer Cell, Kurppa et al. demonstrated that a senescence-like state enables lung cancer cells to survive dual inhibition of EGFR and MEK. This was mediated by the YAP/TEAD pathway, which drives epigenomic reprogramming and EMT to counteract apoptosis. Therapeutic resistance is a primary concern in cancer treatment. Designated targets often acquire mutations that make cancer cells less vulnerable. The Yes-associated protein (YAP) and Transcriptional enhancer factor TEF-1 (TEAD) are conserved downstream effectors of the Hippo pathway that are involved in cancer progression and therapeutic resistance in a variety of cancers. In a study published in this issue of Cancer Cell, Kurppa et al. (2020) provided a deeper understanding on how YAP signaling epigenetically reprograms lung cancer cells, allowing them to escape cell death through dormancy. The implication of this finding opens opportunities to evaluate other cancers with similar phenotypes. With an estimated 142,000 deaths in 2019, lung cancer has the highest rate of mortality in cancer. Over 80% of lung cancers are classified as non-small cell lung cancer (NSCLC). Oncogenic drivers of NSCLC include EGFR and KRAS mutations. EGFR, also known as ErbB1, is a member of a family of 4 receptor tyrosine kinases (ErbB1, ErbB2, ErbB3, and ErbB4), which can be activated by multiple growth factors, including EGF and TGF-a. As a transmembrane protein, EGFR dimerizes upon ligand binding and subsequently transactivates downstream effectors involved in cell proliferation, survival, and migration (Avraham and Yarden, 2011). EGFR tyrosine kinase inhibitors (TKIs) are the standard of care for advanced NSCLC. The clinical outcome has not been very successful, as resistance almost certainly occurs due to mutations abolishing drug binding
or activating alternative pathways (Kobayashi et al., 2005). Multiple approaches have been implemented to overcome resistance, including (1) co-targeting of the extracellular domain and tyrosine kinase domain using anti-EGFR monoclonal antibodies and EGFR TKIs, respectively, and (2) preventing EGFR pathway reactivation by pharmacologically inhibiting key downstream effectors such as RAF, MEK, or ERK. These approaches significantly delay resistance to EGFR but do not reduce recurrence (Tricker et al., 2015), implicating alternative pathways. The Hippo signaling pathway plays a central role in regulating cell fate, proliferation, and apoptosis, mainly by repressing the oncogenic transcription factors YAP and TAZ (Harvey et al., 2013). Previous studies identified YAP as a resistance factor in multiple cancers, including NSCLC, and revealed that the co-inhibition of YAP and MEK can lead to synthetic lethality in tumors harboring BRAF and RAS mutations (Lin et al., 2015). Here, Kurppa et al. (2020) further dissect the mechanisms of resistance following EGFR/MEK co-inhibition in NSCLC bearing EGFR mutations. Kurppa et al. (2020) observed a senescence-like phenotype as a survival strategy for cancer cells following EGFR/ MEK combination treatment. Intriguingly, the senescent phenotype appeared to be reversible, as supported by live imaging and lineage tracing. The authors then identified a strong epigenetic alteration driven by YAP/TEAD in response to EGFR/MEK signaling inhibition. Mecha-
nistically, YAP promotes survival of cancer cells through activation of an epithelial-to-mesenchymal transition (EMT) process, which in turn suppresses the pro-apoptotic factor, Bcl2-modifying factor (BMF). Importantly, the function of YAP/TEAD was verified in xenografts and clinical specimens. The authors also found that cooperation between YAP, TEAD, and the EMT marker SLUG was necessary to repress the pro-apoptotic factor BMF. These results corroborate previous findings on the importance of YAP/TEAD signaling in therapeutic resistance (Yu et al., 2018). Taken together, this novel YAP/TEAD/SLUG/BMF axis represents a connection between epigenetic reprogramming, EMT, and survival as a response to therapeutic stress and demonstrates stress-induced adaptation via activation of alternative pathways in cancer (Figure 1). It remains debatable whether cancer cells can exploit senescence-related processes to enter a dormancy state and endure environmental stresses. By definition, dormancy implies reversibility— dormant cancer cells should maintain the potential to ‘‘wake up.’’ This is seemingly contradictory to the general notion of senescence, which was initially thought of as a permanent cell-cycle arrest (Hanahan and Weinberg, 2000). However, many recent studies argued that senescence can be reversed, and the status of senescence mediators (e.g., p16, p21, RB, and ARF) may change after the senescence process is triggered, allowing cells to resume proliferation (Kuilman et al., 2010). In fact, multiple additional aspects,
Cancer Cell 37, January 13, 2020 ª 2019 Elsevier Inc. 1
Cancer Cell
Previews
Figure 1. Reversibility of YAP/TEAD-Induced Senescence as a Survival Mechanism to Dual Inhibition of EGFR and MEK in Advanced Nonsmall Cell Lung Cancer (NSCLC) Complete inhibition of EGFR/MEK signaling prevents pathway reactivation by maintaining ERK1/2 inactive (middle panel). As a result, cells undergo apoptosis, leading to massive cell death (left panel). Surviving cells adopt a senescent phenotype, which allows them to escape cell death (right panel). This process is mediated by the activation of an alternative pathway, YAP/TEAD signaling, which triggers epigenetic reprogramming and EMT to oppose apoptosis. In the absence of therapeutic pressure, the senescent process is reversed and gives rise to a new ‘‘naive’’ population.
including DNA content, metabolic state, cell-cycle regulators, and lysosomal stress markers, have been characterized to distinguish senescence from transient quiescence (Sharpless and Sherr, 2015). Findings in this work may stimulate further studies to refine our understanding of senescence and cancer cell dormancy, especially under therapeutic settings. Tumor heterogeneity is a major challenge in cancer treatment. In this study (Kurppa et al., 2020), it was shown that the selection for resistant cells was not clonal, as the cells remain sensitive after recovering from therapeutic stress. Interestingly, although the increased expression of YAP following EGFR/MEK inhibition was observed in most cells, the survival was still limited to a rare subset. The authors used a bar-coding experiment to rule out genetic selection as the major determinant of cell survival. However, the process may not be completely stochastic either—it is still possible that the dynamic cellular states (e.g., stem-
2 Cancer Cell 37, January 13, 2020
ness and hybrid EMT) are acting cooperatively to drive the ‘‘selection.’’ It will be interesting to further dissect the regulation of the YAP/TEAD/SLUG/BMF pathway at a single-cell level and examine its interactions with other factors that may together dictate the fates of individual cells.
REFERENCES Avraham, R., and Yarden, Y. (2011). Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat. Rev. Mol. Cell Biol. 12, 104–117. Hanahan, D., and Weinberg, R.A. (2000). The hallmarks of cancer. Cell 100, 57–70.
Kuilman, T., Michaloglou, C., Mooi, W.J., and Peeper, D.S. (2010). The essence of senescence. Genes Dev. 24, 2463–2479. Kurppa, K.J., Liu, Y., To, C., Zhang, T., Fan, M., Vajdi, A., Knelson, E.H., Xie, Y., Lim, K., Cejas, P., et al. (2020). Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 37, this issue, 104–122. Lin, L., Sabnis, A.J., Chan, E., Olivas, V., Cade, L., Pazarentzos, E., Asthana, S., Neel, D., Yan, J.J., Lu, X., et al. (2015). The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet. 47, 250–256. Sharpless, N.E., and Sherr, C.J. (2015). Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408.
Harvey, K.F., Zhang, X., and Thomas, D.M. (2013). The Hippo pathway and human cancer. Nat. Rev. Cancer 13, 246–257.
Tricker, E.M., Xu, C., Uddin, S., Capelletti, M., Ercan, D., Ogino, A., Pratilas, C.A., Rosen, N., €nne, P.A. (2015). Gray, N.S., Wong, K.K., and Ja Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer. Cancer Discov. 5, 960–971.
€nne, Kobayashi, S., Boggon, T.J., Dayaram, T., Ja P.A., Kocher, O., Meyerson, M., Johnson, B.E., Eck, M.J., Tenen, D.G., and Halmos, B. (2005). EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792.
Yu, M., Chen, Y., Li, X., Yang, R., Zhang, L., Huangfu, L., Zheng, N., Zhao, X., Lv, L., Hong, Y., et al. (2018). YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD. Cell Death Dis. 9, 464.
Previews Senesce to Survive: YAP-Mediated Dormancy Escapes EGFR/MEK Inhibition Igor Bado1,2,3 and Xiang H.-F. Zhang1,2,3,4,* 1Lester
and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA 3Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA 4McNair Medical Institute, Baylor College of Medicine, BCM600, One Baylor Plaza, Houston, TX 77030, USA *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2019.12.008 2Dan
Therapeutic resistance is a major challenge in cancer treatment. In this issue of Cancer Cell, Kurppa et al. demonstrated that a senescence-like state enables lung cancer cells to survive dual inhibition of EGFR and MEK. This was mediated by the YAP/TEAD pathway, which drives epigenomic reprogramming and EMT to counteract apoptosis. Therapeutic resistance is a primary concern in cancer treatment. Designated targets often acquire mutations that make cancer cells less vulnerable. The Yes-associated protein (YAP) and Transcriptional enhancer factor TEF-1 (TEAD) are conserved downstream effectors of the Hippo pathway that are involved in cancer progression and therapeutic resistance in a variety of cancers. In a study published in this issue of Cancer Cell, Kurppa et al. (2020) provided a deeper understanding on how YAP signaling epigenetically reprograms lung cancer cells, allowing them to escape cell death through dormancy. The implication of this finding opens opportunities to evaluate other cancers with similar phenotypes. With an estimated 142,000 deaths in 2019, lung cancer has the highest rate of mortality in cancer. Over 80% of lung cancers are classified as non-small cell lung cancer (NSCLC). Oncogenic drivers of NSCLC include EGFR and KRAS mutations. EGFR, also known as ErbB1, is a member of a family of 4 receptor tyrosine kinases (ErbB1, ErbB2, ErbB3, and ErbB4), which can be activated by multiple growth factors, including EGF and TGF-a. As a transmembrane protein, EGFR dimerizes upon ligand binding and subsequently transactivates downstream effectors involved in cell proliferation, survival, and migration (Avraham and Yarden, 2011). EGFR tyrosine kinase inhibitors (TKIs) are the standard of care for advanced NSCLC. The clinical outcome has not been very successful, as resistance almost certainly occurs due to mutations abolishing drug binding
or activating alternative pathways (Kobayashi et al., 2005). Multiple approaches have been implemented to overcome resistance, including (1) co-targeting of the extracellular domain and tyrosine kinase domain using anti-EGFR monoclonal antibodies and EGFR TKIs, respectively, and (2) preventing EGFR pathway reactivation by pharmacologically inhibiting key downstream effectors such as RAF, MEK, or ERK. These approaches significantly delay resistance to EGFR but do not reduce recurrence (Tricker et al., 2015), implicating alternative pathways. The Hippo signaling pathway plays a central role in regulating cell fate, proliferation, and apoptosis, mainly by repressing the oncogenic transcription factors YAP and TAZ (Harvey et al., 2013). Previous studies identified YAP as a resistance factor in multiple cancers, including NSCLC, and revealed that the co-inhibition of YAP and MEK can lead to synthetic lethality in tumors harboring BRAF and RAS mutations (Lin et al., 2015). Here, Kurppa et al. (2020) further dissect the mechanisms of resistance following EGFR/MEK co-inhibition in NSCLC bearing EGFR mutations. Kurppa et al. (2020) observed a senescence-like phenotype as a survival strategy for cancer cells following EGFR/ MEK combination treatment. Intriguingly, the senescent phenotype appeared to be reversible, as supported by live imaging and lineage tracing. The authors then identified a strong epigenetic alteration driven by YAP/TEAD in response to EGFR/MEK signaling inhibition. Mecha-
nistically, YAP promotes survival of cancer cells through activation of an epithelial-to-mesenchymal transition (EMT) process, which in turn suppresses the pro-apoptotic factor, Bcl2-modifying factor (BMF). Importantly, the function of YAP/TEAD was verified in xenografts and clinical specimens. The authors also found that cooperation between YAP, TEAD, and the EMT marker SLUG was necessary to repress the pro-apoptotic factor BMF. These results corroborate previous findings on the importance of YAP/TEAD signaling in therapeutic resistance (Yu et al., 2018). Taken together, this novel YAP/TEAD/SLUG/BMF axis represents a connection between epigenetic reprogramming, EMT, and survival as a response to therapeutic stress and demonstrates stress-induced adaptation via activation of alternative pathways in cancer (Figure 1). It remains debatable whether cancer cells can exploit senescence-related processes to enter a dormancy state and endure environmental stresses. By definition, dormancy implies reversibility— dormant cancer cells should maintain the potential to ‘‘wake up.’’ This is seemingly contradictory to the general notion of senescence, which was initially thought of as a permanent cell-cycle arrest (Hanahan and Weinberg, 2000). However, many recent studies argued that senescence can be reversed, and the status of senescence mediators (e.g., p16, p21, RB, and ARF) may change after the senescence process is triggered, allowing cells to resume proliferation (Kuilman et al., 2010). In fact, multiple additional aspects,
Cancer Cell 37, January 13, 2020 ª 2019 Elsevier Inc. 1
Cancer Cell
Previews
Figure 1. Reversibility of YAP/TEAD-Induced Senescence as a Survival Mechanism to Dual Inhibition of EGFR and MEK in Advanced Nonsmall Cell Lung Cancer (NSCLC) Complete inhibition of EGFR/MEK signaling prevents pathway reactivation by maintaining ERK1/2 inactive (middle panel). As a result, cells undergo apoptosis, leading to massive cell death (left panel). Surviving cells adopt a senescent phenotype, which allows them to escape cell death (right panel). This process is mediated by the activation of an alternative pathway, YAP/TEAD signaling, which triggers epigenetic reprogramming and EMT to oppose apoptosis. In the absence of therapeutic pressure, the senescent process is reversed and gives rise to a new ‘‘naive’’ population.
including DNA content, metabolic state, cell-cycle regulators, and lysosomal stress markers, have been characterized to distinguish senescence from transient quiescence (Sharpless and Sherr, 2015). Findings in this work may stimulate further studies to refine our understanding of senescence and cancer cell dormancy, especially under therapeutic settings. Tumor heterogeneity is a major challenge in cancer treatment. In this study (Kurppa et al., 2020), it was shown that the selection for resistant cells was not clonal, as the cells remain sensitive after recovering from therapeutic stress. Interestingly, although the increased expression of YAP following EGFR/MEK inhibition was observed in most cells, the survival was still limited to a rare subset. The authors used a bar-coding experiment to rule out genetic selection as the major determinant of cell survival. However, the process may not be completely stochastic either—it is still possible that the dynamic cellular states (e.g., stem-
2 Cancer Cell 37, January 13, 2020
ness and hybrid EMT) are acting cooperatively to drive the ‘‘selection.’’ It will be interesting to further dissect the regulation of the YAP/TEAD/SLUG/BMF pathway at a single-cell level and examine its interactions with other factors that may together dictate the fates of individual cells.
REFERENCES Avraham, R., and Yarden, Y. (2011). Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat. Rev. Mol. Cell Biol. 12, 104–117. Hanahan, D., and Weinberg, R.A. (2000). The hallmarks of cancer. Cell 100, 57–70.
Kuilman, T., Michaloglou, C., Mooi, W.J., and Peeper, D.S. (2010). The essence of senescence. Genes Dev. 24, 2463–2479. Kurppa, K.J., Liu, Y., To, C., Zhang, T., Fan, M., Vajdi, A., Knelson, E.H., Xie, Y., Lim, K., Cejas, P., et al. (2020). Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 37, this issue, 104–122. Lin, L., Sabnis, A.J., Chan, E., Olivas, V., Cade, L., Pazarentzos, E., Asthana, S., Neel, D., Yan, J.J., Lu, X., et al. (2015). The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet. 47, 250–256. Sharpless, N.E., and Sherr, C.J. (2015). Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408.
Harvey, K.F., Zhang, X., and Thomas, D.M. (2013). The Hippo pathway and human cancer. Nat. Rev. Cancer 13, 246–257.
Tricker, E.M., Xu, C., Uddin, S., Capelletti, M., Ercan, D., Ogino, A., Pratilas, C.A., Rosen, N., €nne, P.A. (2015). Gray, N.S., Wong, K.K., and Ja Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer. Cancer Discov. 5, 960–971.
€nne, Kobayashi, S., Boggon, T.J., Dayaram, T., Ja P.A., Kocher, O., Meyerson, M., Johnson, B.E., Eck, M.J., Tenen, D.G., and Halmos, B. (2005). EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792.
Yu, M., Chen, Y., Li, X., Yang, R., Zhang, L., Huangfu, L., Zheng, N., Zhao, X., Lv, L., Hong, Y., et al. (2018). YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD. Cell Death Dis. 9, 464.