Skip to main content
An official website of the United States government

SOS signaling in RAS-mutated cancers

, by Erin Sheffels and Rob Kortum

Rob Kortum, MD, PhD, and Erin Sheffels, PhD

Rob Kortum, MD, PhD, and Erin Sheffels, PhD

Rob Kortum earned his Ph.D. with Rob Lewis at the University of Nebraska Medical Center, and trained with both Larry Samelson and Deborah Morrison at NCI.  He is an assistant professor of Pharmacology at Uniformed Services University in Bethesda, MD.  

Erin Sheffels trained with Dr. Kortum and earned her Ph.D. in May 2020.  She plans to do her postdoctoral work with Gina Razidlo at Mayo Clinic.

RAS-mutated tumors were originally thought to proliferate independently of upstream signaling inputs, but we now know that receptor tyrosine kinase-dependent activation of both mutant RAS and non-mutated wild-type (WT) RAS plays an important role in modulating downstream effector signaling and driving therapeutic resistance in RAS-mutated cancers.  The contributions of wild-type RAS to proliferation and transformation in RAS-mutated cancer cells places renewed interest in upstream signaling molecules, including the RasGEFs SOS1 and 2, as potential therapeutic targets in RAS-mutated cancers.

RAS isoforms have a hierarchy of abilities to activate RAS effectors

Mutant RAS-dependent transformation requires both Raf/MEK/ERK and PI3K/AKT effector pathway activation.  However, while HRAS, NRAS, and KRAS can all interact with PI3K and RAF, a series of seminal papers showed that they activate these effectors to different extents, such that there is an inverse relationship in their ability to activate Raf and PI3K: mutant HRAS is a potent activator of PI3K but a poor activator of RAF, and conversely KRAS is a potent activator of Raf but a poor activator of PI3K (1-3).  We are beginning to understand the mechanism for the differential activation of RAF proteins.  The Morrison laboratory recently showed that BRAF preferentially interacts with KRAS via an interaction between the KRAS(4B) polybasic region and an acidic N-terminal region in BRAF (4).  The ability to directly associate with both BRAF and CRAF makes KRAS a more potent activator of the RAF/MEK/ERK cascade.  While the precise mechanism for differential PI3K activation between HRAS and KRAS remains unclear, a major contributor seems to be the polybasic stretch in the hypervariable region of KRAS; mutating basic residues in the KRAS(4B) HVR inhibits Raf/MEK/ERK signaling but enhances PI3K/AKT phosphorylation (5).  These differences in activation abilities impact the dependence of RAS-mutated cancers on upstream signals. For example, PI3K/AKT pathway activation is dependent on RTK signaling in KRAS-mutated colorectal (6) and lung (7) adenocarcinoma cells. A potential role for the WT RAS isoforms is to activate the effector pathways that mutant RAS does not strongly activate, making the cellular outcome a product of signaling by both WT and mutant RAS.  

Mutant RAS can activate WT RAS via SOS

Mutant RAS can activate WT RAS independently of RTK input by at least two interdependent mechanisms.  First, SOS1 can be allosterically activated by RAS, allowing increased activation of WT RAS. When assessing the crystal structure of SOS1, the Kuryian and Bar-Sagi labs found an allosteric RASGTP binding pocket distinct from the SOS1 catalytic domain that, when occupied, relieves SOS1 autoinhibition (8).  This RASGTP binding increases SOS1 catalytic activity by up to 500-fold, setting up a RASGTP−SOS1−WT RAS positive feedback loop that allows for processive localized WT RAS activation at the plasma membrane. Further downstream, PI3K/AKT signaling can phosphorylate eNOS, which can nitrosylate and activate WT HRAS (9). RTK signaling can also activate WT RAS independently from mutant RAS. The McCormick laboratory built on previous work to show that canonical RTK-dependent WT RAS activation supplements basal signaling from mutated RAS to promote proliferation in RAS-mutated tumor cell lines, and combined inhibition of WT and mutated RAS is required to induce cell killing (3, 10).  These mechanisms are not mutually exclusive and may cooperate in some contexts (11-13).

These models all indicate that SOS plays a role in activating WT RAS in mutant RAS cancers. Data from our lab and others suggests that SOS1 and SOS2 may play non-overlapping roles to promote WT RAS activation in RAS mutated tumor cells.  For SOS1, allosteric signaling and RTK-dependent activation are both important for KRAS-mutated cancer cells depending on the cellular context:  SOS1 is required for WT HRAS and NRAS activation in an animal model of KRAS-induced leukemia (14), mutant KRAS−SOS1−WT RAS allosteric signaling promotes growth of KRAS mutant pancreatic cancer cell xenografts (15), and both allosteric signaling and EGFR-SOS1 signaling contribute to growth of KRAS-mutated colorectal cancer cells (16).  In contrast, we found that RTK−SOS2−WT RAS signaling, but not allosteric SOS2 activation, is a critical mediator of PI3K signaling in the context of mutant RAS (17) and protects KRAS-mutated cancer cells from anoikis (18).  

SOS proteins as therapeutic targets in RAS-mutant cancers

In KRAS-mutated cancer cells, single agent MEK inhibitor treatment is ineffective because it relieves ERK-dependent negative feedback signaling, enhancing RTK-SOS-WT RAS signaling to the Raf/MEK/ERK and PI3K/AKT pathways and leading to therapeutic resistance (19-22).  Similar relief of negative feedback signaling drives rapid resistance to KRASG12C inhibitors (23, 24).  In both cases, this resistance is driven by multiple RTKs. CRISPR screens revealed that both KRASG12C inhibitors (25) and MEK inhibitors (26) require either broad inhibition of proximal RTK signaling or targeting of PI3K/mTOR survival signaling to enhance their efficacy and delay therapeutic resistance.  Recent pre-clinical studies showed that co-treatment with allosteric SHP2 inhibitors can overcome both KRASG12C (23, 24) and MEK (27, 28) inhibitor resistance, leading to more durable responses.  Furthermore, we found that SOS2 deletion inhibited RTK-WT RAS-PI3K signaling and synergized with MEK inhibitors in KRAS mutated cell lines (17).

While there are currently no SOS2-specific inhibitors, Bayer Pharmaceuticals published a SOS1 inhibitor suitable for in vitro studies (29).  Furthermore, Boehringer Ingelheim has developed orally available SOS1 inhibitors (30) and started recruiting patients with advanced KRAS-mutated solid tumors in 2019 for a Phase 1 clinical trial (NCT04111458).  SOS1 inhibition is mechanistically most similar to SHP2 inhibition (31), suggesting that SOS1 inhibition could similarly enhance the efficacy of KRASG12C- and MEK-inhibitors.  Indeed this appears to be true for combined SOS1/MEK inhibition, as preliminary data from Boehringer Ingelheim showed marked cooperativity between SOS1- and MEK-inhibition in multiple G12 and G13 KRAS-mutated PDX models (30).  Furthermore, since KRASG12C allosteric inhibitors can only bind KRASGDP, inhibiting SOS1 has the potential advantage of directly enhancing the efficacy of KRASG12C inhibitors by increasing the amount of mutant KRASG12C accessible to drug (29), in addition to inhibiting feedback activation of WT RAS.  While further studies are required, the possibility of inhibiting SOS1 has enormous clinical potential as a combination therapy.

WT RAS signaling is an important modifier of KRAS-mutated oncogenesis, and inhibition of WT RAS signaling may be required for effective treatment of KRAS-mutated cancers.  Understanding the mechanisms by which the ubiquitously expressed RasGEFs SOS1 and SOS2 promote WT RAS activation is an important step in determining the best ways to limit WT RAS signaling.  The ability to pharmacologically manipulate SOS1/2 signaling may lead to optimized therapeutic combinations that can be used to treat KRAS-mutated cancers.

Selected References

  1. Voice JK, Klemke RL, Le A, Jackson JH, 1999. Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J Biol Chem

    [PubMed Abstract]
  2. Yan J, Roy S, Apolloni A, Lane A, Hancock JF, 1998. Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem

    [PubMed Abstract]
  3. Hamilton M, Wolfman A, 1998. Oncogenic Ha-Ras-dependent mitogen-activated protein kinase activity requires signaling through the epidermal growth factor receptor. J Biol Chem

    [PubMed Abstract]
  4. Terrell EM, Durrant DE, Ritt DA, Sealover NE, Sheffels E, Spencer-Smith R, Esposito D, Zhou Y, Hancock JF, Kortum RL, Morrison DK, 2019. Distinct Binding Preferences between Ras and Raf Family Members and the Impact on Oncogenic Ras Signaling. Mol Cell

    [PubMed Abstract]
  5. Zhou Y, Prakash P, Liang H, Cho KJ, Gorfe AA, Hancock JF, 2017. Lipid-Sorting Specificity Encoded in K-Ras Membrane Anchor Regulates Signal Output. Cell

    [PubMed Abstract]
  6. Ebi H, Corcoran RB, Singh A, Chen Z, Song Y, Lifshits E, Ryan DP, Meyerhardt JA, Benes C, Settleman J, Wong KK, Cantley LC, Engelman JA, 2011. Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest

    [PubMed Abstract]
  7. Molina-Arcas M, Hancock DC, Sheridan C, Kumar MS, Downward J, 2013. Coordinate direct input of both KRAS and IGF1 receptor to activation of PI3 kinase in KRAS-mutant lung cancer. Cancer Discov

    [PubMed Abstract]
  8. Margarit SM, Sondermann H, Hall BE, Nagar B, Hoelz A, Pirruccello M, Bar-Sagi D, Kuriyan J, 2003. Structural evidence for feedback activation by Ras.GTP of the Ras-specific nucleotide exchange factor SOS. Cell

    [PubMed Abstract]
  9. Lim KH, Ancrile BB, Kashatus DF, Counter CM, 2008.  Tumour maintenance is mediated by eNOS. Nature

    [PubMed Abstract]
  10. Young A, Lou D, McCormick F, 2013. Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling. Cancer Discov

    [PubMed Abstract]
  11. Boykevisch S, Zhao C, Sondermann H, Philippidou P, Halegoua S, Kuriyan J, Bar-Sagi D, 2006. Regulation of ras signaling dynamics by Sos-mediated positive feedback. Curr Biol

    [PubMed Abstract]
  12. Roose JP, Mollenauer M, Ho M, Kurosaki T, Weiss A, 2007. Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes. Mol Cell

    [PubMed Abstract]
  13. Das J, Ho M, Zikherman J, Govern C, Yang M, Weiss A, Chakraborty AK, Roose JP, 2009. Digital signaling and hysteresis characterize ras activation in lymphoid cells. Cell

    [PubMed Abstract]
  14. You X, Kong G, Ranheim EA, Yang D, Zhou Y, Zhang J, 2018. Unique dependence on Sos1 in KrasG12D -induced leukemogenesis. Blood

    [PubMed Abstract]
  15. Jeng HH, Taylor LJ, Bar-Sagi D, 2012. Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis. Nat Commun

    [PubMed Abstract]
  16. Depeille P, Henricks LM, van de Ven RA, Lemmens E, Wang CY, Matli M, Werb Z, Haigis KM, Donner D, Warren R, Roose JP, 2015. RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth. Nat Cell Biol

    [PubMed Abstract]
  17. Sheffels E, Sealover NE, Wang C, Kim DH, Vazirani IA, Lee E, M Terrell E, Morrison DK, Luo J, Kortum RL, 2018. Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation. Sci Signal

    [PubMed Abstract]
  18. Sheffels E, Sealover NE, Theard PL, Kortum RL, 2019. Anchorage-independent growth conditions reveal a differential SOS2 dependence for transformation and survival in RAS-mutant cancer cells. Small GTPases

    [PubMed Abstract]
  19. Turke AB, Song Y, Costa C, Cook R, Arteaga CL, Asara JM, Engelman JA, 2012. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res

    [PubMed Abstract]
  20. Pettazzoni P, Viale A, Shah P, Carugo A, Ying H, Wang H, Genovese G, Seth S, Minelli R, Green T, Huang-Hobbs E, Corti D, Sanchez N, Nezi L, Marchesini M, Kapoor A, Yao W, Francesco ME, Petrocchi A, Deem AK, Scott K, Colla S, Mills GB, Fleming JB, Heffernan TP, Jones P, Toniatti C, DePinho RA, Draetta GF, 2015. Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. Cancer Res

    [PubMed Abstract]
  21. Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM, Koker M, Heynck S, Stückrath I, Weiss J, Fischer F, Michel K, Goel A, Regales L, Politi KA, Perera S, Getlik M, Heukamp LC, Ansén S, Zander T, Beroukhim R, Kashkar H, Shokat KM, Sellers WR, Rauh D, Orr C, Hoeflich KP, Friedman L, Wong KK, Pao W, Thomas RK, 2009.  Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.

    [PubMed Abstract]
  22. Manchado E, Weissmueller S, Morris JP 4th, Chen CC, Wullenkord R, Lujambio A, de Stanchina E, Poirier JT, Gainor JF, Corcoran RB, Engelman JA, Rudin CM, Rosen N, Lowe SW, 2016. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature

    [PubMed Abstract]
  23. Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A, Qeriqi B, Kim D, Li C, de Stanchina E, Mazutis L, Risso D, Lito P, 2020.  Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature

    [PubMed Abstract]
  24. Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, Hong CB, Corcoran RB, 2020. Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition. Clin Cancer Res

    [PubMed Abstract]
  25. Lou K, Steri V, Ge AY, Hwang YC, Yogodzinski CH, Shkedi AR, Choi ALM, Mitchell DC, Swaney DL, Hann B, Gordan JD, Shokat KM, Gilbert LA, 2019. KRASG12C inhibition produces a driver-limited state revealing collateral dependencies. Sci Signal

    [PubMed Abstract]
  26. Anderson GR, Winter PS, Lin KH, Nussbaum DP, Cakir M, Stein EM, Soderquist RS, Crawford L, Leeds JC, Newcomb R, Stepp P, Yip C, Wardell SE, Tingley JP, Ali M, Xu M, Ryan M, McCall SJ, McRee AJ, Counter CM, Der CJ, Wood KC, 2017. A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution. Cell Rep

    [PubMed Abstract]
  27. Fedele C, Ran H, Diskin B, Wei W, Jen J, Geer MJ, Araki K, Ozerdem U, Simeone DM, Miller G, Neel BG, Tang KH, 2018. SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models. Cancer Discov

    [PubMed Abstract]
  28. Ruess DA, Heynen GJ, Ciecielski KJ, Ai J, Berninger A, Kabacaoglu D, Görgülü K, Dantes Z, Wörmann SM, Diakopoulos KN, Karpathaki AF, Kowalska M, Kaya-Aksoy E, Song L, van der Laan EAZ, López-Alberca MP, Nazaré M, Reichert M, Saur D, Erkan MM, Hopt UT, Sainz B Jr, Birchmeier W, Schmid RM, Lesina M, Algül H, 2018. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med

    [PubMed Abstract]
  29. Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, Werbeck ND, Briem H, Boemer U, Weiske J, Badock V, Mastouri J, Petersen K, Siemeister G, Kahmann JD, Wegener D, Böhnke N, Eis K, Graham K, Wortmann L, von Nussbaum F, Bader B, 2019. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci U S A

    [PubMed Abstract]
  30. Gerlach D, Gmachl M, Ramharter J, The J, Fu S-C, Trapani F, Kessler D, Rumpel K, Botesteanu D-A, Ettmayer P, Arnhof H, Gerstberger T, Kofink C, Wunberg T, Vellano CP, Heffernan TP, Marszalek JR, Pearson M, McConnell DB, Kraut N, Hofmann MH, 2020. BI-3406 and BI 1701963: Potent and selective SOS1::KRAS inhibitors induce regressions in combination with MEK inhibitors or irinotecan. AACR Virtual Meeting 1, abstract currently unavailable.

  31. Nichols RJ, Haderk F, Stahlhut C, Schulze CJ, Hemmati G, Wildes D, Tzitzilonis C, Mordec K, Marquez A, Romero J, Hsieh T, Zaman A, Olivas V, McCoach C, Blakely CM, Wang Z, Kiss G, Koltun ES, Gill AL, Singh M, Goldsmith MA, Smith JAM, Bivona TG, 2018. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol

    [PubMed Abstract]
< Older Post

RAS Mutation Tropism

Newer Post >

Deploying a RAS pipeline against the SARS-CoV-2 pandemic

If you would like to reproduce some or all of this content, see Reuse of NCI Information for guidance about copyright and permissions. In the case of permitted digital reproduction, please credit the National Cancer Institute as the source and link to the original NCI product using the original product's title; e.g., “SOS signaling in RAS-mutated cancers was originally published by the National Cancer Institute.”

Archive

Email