Oncogenic RAS promotes MYC protein stability by upregulating the expression of the inhibitor of apoptosis protein family member Survivin

Abstract

The small GTPase KRAS is frequently mutated in pancreatic cancer and its cooperation with the transcription factor MYC is essential for malignant transformation. The key to oncogenic KRAS and MYC working together is the stabilization of MYC expression due to KRAS activating the extracellular signal–regulated kinase 1/2, which phosphorylates MYC at serine 62 (Ser 62). This prevents the proteasomal degradation of MYC while enhancing its transcriptional activity. Here, we identify how this essential signaling connection between oncogenic KRAS and MYC expression is mediated by the inhibitor of apoptosis protein family member Survivin. This discovery stemmed from our finding that Survivin expression is downregulated upon treatment of pancreatic cancer cells with the KRASG12C inhibitor Sotorasib. We went on to show that oncogenic KRAS increases Survivin expression by activating extracellular signal–regulated kinase 1/2 in pancreatic cancer cells and that treating the cells either with siRNAs targeting Survivin or with YM155, a small molecule that potently blocks Survivin expression, downregulates MYC and strongly inhibited their growth. We further determined that Survivin protects MYC from degradation by blocking autophagy, which then prevents cellular inhibitor of protein phosphatase 2A from undergoing autophagic degradation. Cellular inhibitor of protein phosphatase 2A, by inhibiting protein phosphatase 2A, helps to maintain MYC phosphorylation at Ser 62, thereby ensuring its cooperation with oncogenic KRAS in driving cancer progression. Overall, these findings highlight a novel role for Survivin in mediating the cooperative actions of KRAS and MYC during malignant transformation and raise the possibility that targeting Survivin may offer therapeutic benefits against KRAS-driven cancers. The small GTPase KRAS is frequently mutated in pancreatic cancer and its cooperation with the transcription factor MYC is essential for malignant transformation. The key to oncogenic KRAS and MYC working together is the stabilization of MYC expression due to KRAS activating the extracellular signal–regulated kinase 1/2, which phosphorylates MYC at serine 62 (Ser 62). This prevents the proteasomal degradation of MYC while enhancing its transcriptional activity. Here, we identify how this essential signaling connection between oncogenic KRAS and MYC expression is mediated by the inhibitor of apoptosis protein family member Survivin. This discovery stemmed from our finding that Survivin expression is downregulated upon treatment of pancreatic cancer cells with the KRASG12C inhibitor Sotorasib. We went on to show that oncogenic KRAS increases Survivin expression by activating extracellular signal–regulated kinase 1/2 in pancreatic cancer cells and that treating the cells either with siRNAs targeting Survivin or with YM155, a small molecule that potently blocks Survivin expression, downregulates MYC and strongly inhibited their growth. We further determined that Survivin protects MYC from degradation by blocking autophagy, which then prevents cellular inhibitor of protein phosphatase 2A from undergoing autophagic degradation. Cellular inhibitor of protein phosphatase 2A, by inhibiting protein phosphatase 2A, helps to maintain MYC phosphorylation at Ser 62, thereby ensuring its cooperation with oncogenic KRAS in driving cancer progression. Overall, these findings highlight a novel role for Survivin in mediating the cooperative actions of KRAS and MYC during malignant transformation and raise the possibility that targeting Survivin may offer therapeutic benefits against KRAS-driven cancers. The RAS family of small GTPases, including KRAS, HRAS, and NRAS, function as molecular switches that are tightly controlled and transduce signals between cell surface receptor tyrosine kinases and effectors that regulate several cellular processes, including cell growth, migration, attachment, differentiation, and survival (1Herdeis L. Gerlach D. McConnell D.B. Kessler D. Stopping the beating heart of cancer: KRAS reviewed.Curr. Opin. Struct. Biol. 2021; 71: 136-147Crossref PubMed Scopus (27) Google Scholar, 2Waters A.M. Der C.J. Kras: the critical driver and therapeutic target for pancreatic cancer.Cold Spring Harb Perspect. Med. 2018; 8: 1-18Crossref Scopus (472) Google Scholar). However, the different RAS isoforms are also frequently mutated in cancer, resulting in their constitutive activation. For example, KRAS is mutated in nearly 95% of all pancreatic ductal adenocarcinoma (PDAC) patients, a particularly aggressive and deadly form of cancer (2Waters A.M. Der C.J. Kras: the critical driver and therapeutic target for pancreatic cancer.Cold Spring Harb Perspect. Med. 2018; 8: 1-18Crossref Scopus (472) Google Scholar, 3Hobbs G.A. Der C.J. Rossman K.L. RAS isoforms and mutations in cancer at a glance.J. Cell Sci. 2016; 129: 1287-1292Crossref PubMed Scopus (584) Google Scholar), where it has been shown to potently activate extracellular signal–regulated kinase 1/2 (ERK1/2) and PI3K and give rise to enhanced cell growth, chemoresistance, migration, and invasion, as well as metastatic spread. Treatment of PDAC cells with recently developed inhibitors that target specific oncogenic KRAS mutants, that is, Sotorasib, Adagrasib, and MRTX1133, or block different components of the ERK1/2 or PI3K pathways (4Stalnecker C.A. Der C.J.R.A.S. Wanted dead or alive: advances in targeting RAS mutant cancers.Sci. Signal. 2020; 13: 1-7Crossref Scopus (54) Google Scholar, 5Conway J.R. Herrmann D. Evans T.J. Morton J.P. Timpson P. Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine.Gut. 2019; 68: 742-758Crossref PubMed Scopus (53) Google Scholar, 6Wang X. Allen S. Blake J.F. Bowcut V. Briere D.M. Calinisan A. et al.Identification of MRTX1133, a noncovalent, potent, and selective KRASG12DInhibitor.J. Med. Chem. 2022; 65: 3123-3133Crossref PubMed Scopus (181) Google Scholar), cause the cells to lose their aggressive phenotypes, underscoring the importance of RAS signaling in cancer progression (7Lanman B.A. Allen J.R. Allen J.G. Amegadzie A.K. Ashton K.S. Booker S.K. et al.Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors.J. Med. Chem. 2020; 63: 52-65Crossref PubMed Scopus (354) Google Scholar, 8Hallin J. Engstrom L.D. Hargis L. Calinisan A. Aranda R. Briere D.M. et al.The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients.Cancer Discov. 2020; 10: 54-71Crossref PubMed Scopus (711) Google Scholar, 9Hayes T.K. Neel N.F. Hu C. Gautam P. Chenard M. Long B. et al.Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression.Cancer Cell. 2016; 29: 75-89Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). However, PDAC patients often become resistant to therapies, highlighting the continued need to better understand how KRAS mediates its oncogenic effects. In order for RAS to transform primary cells, it needs to cooperate with another proto-oncogene, often the transcription factor MYC (9Hayes T.K. Neel N.F. Hu C. Gautam P. Chenard M. Long B. et al.Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression.Cancer Cell. 2016; 29: 75-89Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 10Kerkhoff E. Houben R. Löffler S. Troppmair J. Lee J.E. Rapp U.R. Regulation of c-myc expression by Ras/Raf signalling.Oncogene. 1998; 16: 211-216Crossref PubMed Scopus (122) Google Scholar, 11Vaseva A.v. Blake D.R. Gilbert T.S.K. Ng S. Hostetter G. Azam S.H. et al.KRAS suppression-induced degradation of MYC is antagonized by a MEK5-ERK5 compensatory mechanism.Cancer Cell. 2018; 34: 807-822.e7Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), as originally demonstrated in a landmark study, where only after coexpressing oncogenic HRAS with MYC in primary fibroblasts did the cells exhibit the characteristics of cancer cells, that is, loss of contact inhibition, anchorage-independent growth, and tumor formation in mice (12Sears R. Leone G. DeGregori J. Nevins J.R. Ras enhances myc protein stability.Mol. Cell. 1999; 3: 169-179Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar). The importance of MYC in RAS-induced cellular transformation further by that oncogenic RAS increases MYC protein expression by its degradation (9Hayes T.K. Neel N.F. Hu C. Gautam P. Chenard M. Long B. et al.Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression.Cancer Cell. 2016; 29: 75-89Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, R. Leone G. DeGregori J. Nevins J.R. Ras enhances myc protein stability.Mol. Cell. 1999; 3: 169-179Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar). of this the phosphorylation of MYC R. E. Nevins J.R. phosphorylation pathways regulate protein PubMed Scopus Google Scholar). The of ERK1/2 by KRAS in the phosphorylation of MYC at Ser 62, which the cellular expression of MYC and enhances its transcriptional of in transcriptional and Biol. 16: PubMed Scopus Google Scholar, MYC Spring Harb Perspect. Med. Scopus Google Scholar, B. M. A. G. M. et phosphorylation is for cellular to Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In cells that oncogenic MYC is on by kinase which then helps to the protein phosphatase 2A resulting in the of Ser 62 and thereby targeting MYC for degradation in the MYC Spring Harb Perspect. Med. Scopus Google Scholar, J. pathways by the tumor in Med. Full Text Full Text PDF PubMed Scopus Google Scholar, J. D.B. G. et to the therapeutic of this J. 2016; PubMed Scopus Google Scholar). However, in cancer cells oncogenic of KRAS, the between the of MYC is toward phosphorylation at Ser 62, the MYC that and degradation. Here, we show that essential of the signaling pathway by which oncogenic KRAS enhances MYC expression is the protein which is a member of the inhibitor of apoptosis protein Survivin is at in Survivin at a glance.J. Cell Sci. 2019; Scopus Google Scholar, B. A. Survivin in cancer: novel PubMed Scopus Google its expression is in a of where it is for by inhibiting the of Survivin at a glance.J. Cell Sci. 2019; Scopus Google Scholar, A. et of a 8: Google Scholar, K.L. et cancer cells survival by in 2021; PubMed Scopus Google Scholar). Survivin has also been to cell migration, as well as autophagy, a by which cellular components are for degradation in Survivin at a glance.J. Cell Sci. 2019; Scopus Google Scholar, Lee et and and in cancer J. PubMed Scopus Google Scholar, S.H. S. et is a novel and in cancer and mouse 2020; 16: PubMed Scopus Google Scholar, A. Survivin protein with in and PubMed Scopus Google Scholar, J. Survivin of and apoptosis and novel target for cancer PubMed Scopus Google Scholar, G. Survivin mediates targeting of the to the and PubMed Scopus Google Scholar, A. L. A. E. A. X. et of the of cancer cells by Cell. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). In this we identify a novel role for Survivin in the of oncogenic KRAS to malignant transformation. We how Survivin expression is in PDAC cells and cells K.L. et cancer cells survival by in 2021; PubMed Scopus Google Scholar, A. of degradation of PubMed Scopus Google and that its siRNAs or by treatment with YM155, a small molecule that potently Survivin blocks their growth A. D. C. M. C. et and how is the PubMed Scopus Google Scholar, A. M. M. et a novel of tumor PubMed Scopus Google Scholar). We then the by which Survivin mediates the of oncogenic KRAS on the phosphorylation and cellular of its to block the autophagic degradation of a protein that and protects MYC from by ensuring the phosphorylation of MYC at Ser 62 B. C.J. X. S. et inhibitors of the tumor for the treatment of pancreatic PubMed Scopus Google Scholar, P. M. R. et in Full Text Full Text PDF PubMed Scopus Google Scholar, B. The role of in cancer: a and PubMed Scopus Google Scholar). This then how oncogenic KRAS, by signaling the of Survivin expression, enhances the cellular expression and transcriptional of thereby the for oncogenic KRAS and MYC to together to oncogenic transformation. better understand how oncogenic KRAS malignant we determined the of treating PDAC cells with which and the oncogenic KRASG12C The growth of the cells to treatment with the inhibitor We also determined that the expression of the cell growth and survival protein Survivin strongly downregulated these that Survivin role in the of oncogenic KRAS to transform We recently that the oncogenic in in mouse fibroblasts it strongly Survivin expression K.L. et cancer cells survival by in 2021; PubMed Scopus Google Scholar). We then this also the in mouse PDAC cell to form of this oncogenic KRAS mutant upon treatment of and cells with the of Survivin expression with expression the of oncogenic RAS to activate ERK transcription and that cell growth and survival (2Waters A.M. Der C.J. Kras: the critical driver and therapeutic target for pancreatic cancer.Cold Spring Harb Perspect. Med. 2018; 8: 1-18Crossref Scopus (472) Google Scholar), we determined ERK for the Survivin expression in PDAC cells mutant of and cells to as well as and cell with the ERK1/2 inhibitor for ERK1/2 expression between the different cell the of protein cell by treatment with the with the of cells, which a in ERK1/2 expression However, ERK1/2 in the cells by as determined that the form of ERK1/2 where ERK1/2 a in Survivin expression the importance of Survivin in cancer cell we of YM155, which Survivin expression by blocking the transcription and factor X. A. A. et of by of in the J. Biol. 3: Google Scholar, M. M. M. M. et factor is a target of YM155, a of Cell Full Text Full Text PDF PubMed Scopus Google Scholar). Treatment of and cells with for a in Survivin expression these cell with of YM155, a in cell growth further the actions of we determined PDAC cells of Survivin the expression of with in RAS-induced cellular transformation. is the transcription factor and which is in where it has been shown to different of cancer progression. and cells with either 2A, or different siRNAs that target Survivin and a in the of MYC 2A and in MYC expression also and cells with Survivin expression of Survivin in to MYC findings how of Survivin expression cause MYC to on that Survivin expression J.G. M. C. D. et expression tumor enhanced 13: PubMed Scopus Google Scholar, S. J. P. M. Hu P. et with molecular and of cells 29: PubMed Scopus Google Scholar, A. and expression of in cells in cells a role for in Cell Full Text Full Text PDF PubMed Scopus Google Scholar), we that this due to a in the transcription of the MYC However, this is the as on from and cells a in MYC to cells it that upon of cells for the in MYC protein expression by its We then Survivin the of the MYC with MYC either or with YM155, and the resulting expression of determined for to the expression of in cells, expression of in cells The that Survivin downregulated and MYC that Survivin enhances MYC expression by its We inhibited of the degradation in cells, and in order to this the of Survivin on MYC Treatment of and cells with the inhibitor a in MYC expression and for cell with that MYC in MYC Spring Harb Perspect. Med. Scopus Google Scholar, B. M. A. G. M. et phosphorylation is for cellular to Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. pathways by the tumor in Med. Full Text Full Text PDF PubMed Scopus Google Scholar, J. D.B. G. et to the therapeutic of this J. 2016; PubMed Scopus Google Scholar). However, we that the in MYC expression by treating cells with by treatment and for cell that the of Survivin to MYC expression to a of proteasomal degradation. We then determined inhibiting the of to MYC The of MYC in and cells with or and YM155, nearly and for cell The in MYC expression by the of Survivin also by treatment with with the that Survivin role in degradation of Survivin expression in cells with and is to these cells with This that in these cancer cells, the cellular of Survivin is of that its to autophagic degradation its expression to further a role for Survivin in blocking and thereby to MYC expression, In of cells with MYC and of the protein either or with for by In the cells, while the However, treatment of the cells and to together in the in that these also for as by the of that in these In the of from and cells with for in the expression of the protein also to as in cells is while its expression the of are cells of Survivin treatment with downregulated the expression of In the of autophagic in and cells of Survivin determined by the in the of the which and This of the that is to in which with The of a loss in which is to autophagic that treatment of either cell with a in autophagic Survivin from the cells siRNAs and these findings strongly that Survivin the of MYC by degradation. is well that the of MYC is tightly controlled by its phosphorylation on Ser 62, MYC is from degradation. However, phosphorylation of in the of Ser 62, targeting MYC for degradation MYC Spring Harb Perspect. Med. Scopus Google Scholar). we to Survivin the of MYC by its phosphorylation and cells with a of and for either or and then to MYC expression in these cells strongly downregulated of treatment and for cell its expression by treatment with the Survivin expression inhibited and for cell these with YM155, we that the of MYC phosphorylation at Ser 62 while phosphorylation of and and for cell and The that has on the phosphorylation of MYC at Ser 62 by a loss of ERK1/2 treating these cells with YM155, or with to ERK1/2 phosphorylation and while treating the cells with together with for to maintain a of MYC expression, to cells with phosphorylation at Ser 62 that Survivin also a role in the phosphorylation of a key that the cellular of of Ser 62 in MYC is mediated by MYC Spring Harb Perspect. Med. Scopus Google Scholar), we its expression by cells of Survivin. is of different and J. D.B. G. et to the therapeutic of this J. 2016; PubMed Scopus Google Scholar, as a of the cell Biol. 2016; PubMed Scopus Google Scholar), and the expression of in cells and in cells with However, we that a protein that is in cancers and shown to MYC and from Ser downregulated upon treatment with either and for cell or siRNAs that target Survivin expression in a in MYC that to the cells of Survivin or We then to Survivin expression by inhibiting activity. treatment of PDAC cells with increases and downregulates expression, we how the of cells of Survivin with the inhibitor shown in and for cell and treatment of and cells with to the of and on we that treating cells a form of with its expression, while treatment this and on from and cells of Survivin a in to cells findings that Survivin the expression of by its transcription as well as by the protein from degradation. We shown that PDAC cells of Survivin inhibited their growth. MYC are also this we cells of Survivin by the expression of However, MYC in cells with in its degradation and only cell growth we growth on cells with and that Survivin expression inhibited while MYC cells with or of shown to their growth by treating the cells with either or of and their growth to and to with cells further the importance of MYC for cell growth inhibition, we the small molecule inhibitor which with the of MYC to function as a transcription factor by the formation of D.M. J. et and in and of a novel inhibitor of PubMed Scopus Google Scholar). cells and cells with to their growth by at and the of to the growth by the treatment of and cells with the cells also with that PDAC cells are on Survivin to maintain MYC expression and their growth. KRAS is mutated in a of PDAC and models and of this it as the driver of PDAC and progression (1Herdeis L. Gerlach D. McConnell D.B. Kessler D. Stopping the beating heart of cancer: KRAS reviewed.Curr. Opin. Struct. Biol. 2021; 71: 136-147Crossref PubMed Scopus (27) Google Scholar, 2Waters A.M. Der C.J. Kras: the critical driver and therapeutic target for pancreatic cancer.Cold Spring Harb Perspect. Med. 2018; 8: 1-18Crossref Scopus (472) Google Scholar). This has to a of to target KRAS, or its as a cancer that and specific oncogenic KRAS are of the and in the which KRASG12C and is (7Lanman B.A. Allen J.R. Allen J.G. Amegadzie A.K. Ashton K.S. Booker S.K. et al.Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors.J. Med. Chem. 2020; 63: 52-65Crossref PubMed Scopus (354) Google Scholar). inhibitors shown in treating different of cancer, nearly all therapeutic that been to KRAS, or effectors of KRAS the and signaling to a S. A. M. et al.KRAS mutations that to KRAS and Adagrasib, and from in 2021; 16: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. et to KRAS inhibition in J. Med. 2021; PubMed Scopus Google Scholar). to a better of the by which oncogenic of KRAS cancer with the that this highlight therapeutic for we PDAC cells with and that the expression of Survivin in these cells strongly This to the importance of Survivin in which to our discovery of a novel by which Survivin oncogenic to the expression of MYC expression during PDAC progression. on the findings in this study, provides a of how Survivin a critical role in the of oncogenic KRAS to MYC with oncogenic KRAS the protein kinase that in the of This in the of Survivin expression, as well as the phosphorylation of MYC at Ser 62, which enhances the of MYC to function as a transcription factor and its cellular expression (9Hayes T.K. Neel N.F. Hu C. Gautam P. Chenard M. Long B. et al.Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression.Cancer Cell. 2016; 29: 75-89Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, R. E. Nevins J.R. phosphorylation pathways regulate protein PubMed Scopus Google Scholar, B. M. A. G. M. et phosphorylation is for cellular to Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. et to KRAS inhibition in J. Med. 2021; PubMed Scopus Google Scholar). in cells, MYC is on by kinase which in the phosphatase that the of Ser 62, targeting MYC for and proteasomal degradation MYC Spring Harb Perspect. Med. Scopus Google Scholar). However, the of Survivin expression by oncogenic KRAS provides a to the phosphorylation of MYC at Ser 62 and that its expression is this is due to the of Survivin to block and inhibitor of from undergoing autophagic degradation. This finding is in with a that is a that A.M. prevents cellular transformation by MYC proteasomal 13: PubMed Scopus Google Scholar). the expression of Survivin that the phosphorylation of MYC at Ser 62 is thereby MYC from to the where it is by blocking autophagy, Survivin also prevents MYC from to this for degradation that for the of MYC to to for the specific by Survivin to block autophagy, of this may its to with several including and Lee et and and in cancer J. PubMed Scopus Google Scholar, S.H. S. et is a novel and in cancer and mouse 2020; 16: PubMed Scopus Google Scholar, J. P. as a target for inhibition in 2016; PubMed Scopus Google Scholar). these findings how Survivin as a critical signaling in the of oncogenic KRAS to regulate MYC expression, by it from at a key and by inhibiting a specific together with our that Survivin is essential for the actions of by aggressive and pancreatic cancer cells, highlight how this RAS signaling target the and survival of tumor cells as well as the tumor K.L. et cancer cells survival by in 2021; PubMed Scopus Google Scholar, The of in from cancer cells with cell survival and 2016; 8: PubMed Scopus Google Scholar). further that targeting Survivin as of a to increases in MYC expression is with in PDAC S. J. et to KRAS inhibition in J. Med. 2021; PubMed Scopus Google Scholar, A. J. et associated with to 2021; PubMed Scopus Google Scholar, E. A. G. M. E. et al.The of in primary pancreatic ductal 2019; PubMed Scopus Google Scholar), with the are that target MYC V. targeting of 2022; Full Text Full Text PDF PubMed Scopus Google Scholar, J.R. L. The to a inhibitor to the Cell Biol. 2021; PubMed Scopus Google Scholar). has been shown to well by cancer patients in M. R. A. et of YM155, a novel in patients with solid PubMed Scopus Google Scholar, A. A. G. A. E. et of with and in patients with Full Text Full Text PDF PubMed Scopus Google Scholar). it of to in with as to cells in with at The mouse and PDAC cell as and to by C.A. S. E. et pancreatic of Full Text Full Text PDF PubMed Scopus Google Scholar). cells in and to the to The and PDAC cell as well as the in expression Survivin MYC E. D. A. J.E. D. et al.The of myc with Cell. 2016; 29: Full Text Full Text PDF PubMed Scopus (53) Google Scholar), J. J. et is with tumor PubMed Scopus Google Scholar), MYC J. S. C. D. expression in cancer PubMed Scopus Google Scholar), and L. The of from formation to with PubMed Scopus Google and PDAC cells the Survivin expression in mouse cell mouse Survivin while for the of Survivin in cell siRNAs targeting Survivin and in all siRNAs and cells with the of or of and and by the The on protein on a to and the to The in and at with of the from Cell which is in ERK MYC RAS Survivin and and The then with Cell Cell for with with and developed and a or a The from cells with YM155, or for the to and on the a and the The to MYC and from by cells with the and as well as The the after and and with to target the on and with The cells in to cells to their and the on and a with a and The the as K.L. C.A. D. J.E. S. et of ERK and inhibition as a treatment for pancreatic Med. 2019; PubMed Scopus Google and to The cells in and with or on the either a or with a a and a to the of to which with it to in the of degradation. to the of the which is as autophagic for the and of for 2021; PubMed Scopus Google Scholar). how this is K.L. C.A. D. J.E. S. et of ERK and inhibition as a treatment for pancreatic Med. 2019; PubMed Scopus Google Scholar, for the and of for 2021; PubMed Scopus Google Scholar). in well of a with the and of YM155, Sotorasib, or of to well and for The by a at of a of and as of the findings determined and are the This The that of with the of this We Hu in for We also for the L. R. A. and M. A. A. E. A. L. R. A. and M. A. A. L. R. A. and M. A. A. L. R. A. and M. A. A. This by to R. A. M. A. and L. the the and

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