Skip to main content

SHP2 Inhibitors for Treating Cancer

, by Suman Mukhopadhyay, Carmine Fedele and Benjamin G Neel

Suman Mukhopadhyay PhD, Carmine Fedele PhD, and Benjamin G. Neel MD PhD

Suman Mukhopadhyay PhD, Carmine Fedele PhD, and Benjamin G. Neel MD PhD

The research was performed at the Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, where Benjamin G Neelis the Director. Carmine Fedeleis now at the Oncology Department of Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, and Suman Mukhopadhyay is a postdoc in the Perlmutter Cancer Center, New York University Langone Health, New York.

Decades of research have identified mutations that constitutively activate proto-oncogenes in various types of cancer. KRAS (and to a lesser extent, other RAS isoforms) is among the most frequently mutated driver oncogenes and is often associated with therapeutic resistance and poor prognosis [1-3]. KRAS mutations are seen in nearly 20% of all patients presenting to major cancer centers, including >90%, 50%, and 25–30% of pancreas, colon, and non-small cell lung cancers, respectively [4, 5]. Mutant KRAS activates a complex array of pathways, in which cross-talk, feedback loops, branch points, and multi-component signaling complexes are recurrent features [1, 6]. Although several attempts been made to use potent and selective inhibitors of the ERK MAPK cascade (RAF/MEK/ERK) to target RAS-mutant malignancies, the efficacy of these small molecules is often negated by activation of upstream signaling mediated by these feedback loops, which results in ERK reactivation [7]. On the other hand, targeting parallel signaling pathways (PI3K/mTOR + MEK) has been limited by toxicity [8]. 

Earlier studies showed that MEK-inhibitor (MEKi) treatment of KRAS-mutant cancers results in “adaptive resistance”, characterized by induction of genes encoding receptor tyrosine kinases (RTKs) and/or their ligands [9-11]. Distinct RTK ligands are induced in different tumors, even within a single histotype, making it difficult to improve outcomes by combining RTK and MEK inhibitors. SHP2, a ubiquitously expressed non-receptor protein-tyrosine phosphatase encoded by the PTPN11 gene, lies downstream of almost all RTKs and is required for RTK-evoked RAS activation [12]. These features suggested that SHP2 inhibitors (SHP2i) might be attractive candidates for combination therapy to enhance MEK inhibitor (MEKi) action in KRAS-driven cancers. Subsequently, multiple  groups, including ours  [13-18], provided pre-clinical data supporting the idea of tackling “adaptive resistance” to MEKi by using SHP2i. Several pharmaceutical companies have developed SHP2 inhibitors, with multiple agents, including TNO155, RMC-4630, JAB-3068, RLY-1971, ERAS-601, and BBP-398, currently in phase 1/2 trials. One of these, RMC-4630, has been combined with MEKi in patients, and responses have been reported (7 patients treated, 1 stable disease, 1 partial response), but this combination might ultimately be limited by toxicity [19].

KRASG12C mutant with SHP2 + KRASG12C inhibitors

Pairing SHP2i with a mutant-selective agent might be a more promising therapeutic strategy, as it would limit the toxicity of “vertical” pathway inhibition seen with MEKi/SHP2i combinations. Previous studies showed that after MEKi-treatment of KRAS-mutant cancer cells, SHP2is prevent MEK/ERK pathway reactivation at the level of SOS1/2 [13, 18]. KRAS mutants differentially affect the RAS-GTP/GDP cycle, with some (most notably, KRASG12C) retaining significant intrinsic GTPase activity, although they remain defective in, or impervious to, RAS-GAP action [20, 21]. The residual GTPase activity in such “cycling mutants'' renders them dependent on SOS1/2 activity (exchange of GDP for GTP). Accordingly, in the MEKi/SHP2i combination studies, SHP2i efficacy correlated with the level of residual GTPase activity [13, 18], with SHP2is  showing significant single agent activity against KRASG12C-mutant cancer cells [18, 22]. 

Long considered “undruggable”, the pioneering work of Kevan Shokat opened the door to the development of mutant KRAS-specific inhibitors, particularly targeting KRASG12C [23].These landmark developments have led to several clinical grade KRASG12C inhibitors, the most advanced of which (AMG510, MRTX849) have shown significant single agent efficacy, particularly in NSCLC patients [24-27]. Lessons learned from studies of other targeted agents [9, 28, 29], including other inhibitors in the RAS/ERK pathway, suggested that drug resistance will also limit the effects of KRASG12C inhibitors (hereafter, G12Cis). This prediction has now been borne out in multiple pre-clinical studies [30-35], as well as in the clinical data reported on AMG510 and MRTX849 [36, 37]. Delineating G12Ci resistance mechanisms is essential for developing ways to prevent or combat their emergence.  

Recent studies by others [25, 31, 32, 35, 38], along with our recent report [22], reveal that KRAS-mutant cancer cells develop adaptive resistance to G12C inhibitors (G12Ci). As is the case following exposure to other RAS/ERK pathway inhibitors (BRAFis/MEKis), genes encoding several RTKs/RTK ligands are induced upon G12Ci treatment. The addition of SHP2is improves G12Ci efficacy in several ways. First, G12Cis target the GDP-bound state of KRAS (KRAS-GDP). Effectively, then, G12Ci action is opposed by RAS-GEF activity. By preventing SOS1/2 action, SHP2is increase the amount of KRAS-GDP and thus the “target” of G12Cis [13, 22]. SHP2is also inhibit reactivation of other, wild type RAS isoforms (encoded by the other, normal, KRAS allele and/or H/NRAS) [31]. Consistent with these actions, SOS inhibitors also potentiate G12Ci action. For example, BAY-293, a potent SOS1 inhibitor, synergizes with ARS-853 to inhibit RAS activation and cell proliferation [39]. 

Most of the above studies on RAS/ERK pathway combinations either used standard cancer cell lines, cell-derived xenografts (CDXs), or patient-derived xenografts (PDXs).  Such models, of course, lack a functional immune system and thus a bona fide tumor microenvironment (TME). Cancer cells and cells in the TME engage in multiple, complex, multi-dimensional interactions that affect tumor behavior and drug response [40, 41]. In our view, curative cancer therapies almost certainly require the generation of durable anti-tumor immune response. Viewed through this lens, the  inability of any current targeted therapy/therapeutic combination to achieve cure reflects the failure of these strategies to generate such a response. Consequently, understanding the effects of any new agent/combination on tumor cells and the TME is essential if we are to move from responses to cures. This issue is particularly important for understanding the effects of inhibitors of targets that, like SHP2, act on immune receptor and cytokine signaling as well as RTK pathways in multiple TME cell types  [42].

To this end, we investigated the cell-autonomous and non-autonomous effects of SHP2is alone and combined with G12Cis in syngeneic, genetically engineered mouse models (GEMMs) of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) [22].  As expected, each agent/combination had some similar effects in the two models. In both, the G12Ci/SHP2i combination elicited apparently favorable effects on the immune TME, decreasing myeloid suppressor cells, increasing total and CD8+ T cells and in most, also increasing intratumor B cells. In both models, intratumor T cells showed evidence of “exhaustion”, and anti-tumor efficacy in the PDAC model could be enhanced by addition of anti-PD1 antibodies to the G12Ci/SHP2i combination.  

Other responses were quite different between these models. For example, as we reported in our earlier studies of MEKi/SHP2i combinations in PDAC [18], SHP2i alone had anti-angiogenic and anti-fibrotic effects in the PDAC model. By contrast, angiogenesis was increased in lung tumors from mice treated with single agent SHP2i or G12Ci/SHP2i combinations. The two NSCLC models, KRASG12C (KC) and KrasG12C;Tp53R270H(KCP), also differed in overall response and detailed effects on the TME.  

To begin to deconvolve the locus of SHP2i action in the PDAC model, we generated tumors from cells reconstituted with a drug-resistant PTPN11 mutant (PTPN11T253M/Q257L). Tumors from cells expressing this mutant failed to regress or show influx of CD8+ or CD4+ lymphocytes upon SHP2i treatment. This lack of anti-tumor immune response correlated with (and was likely caused by) failure to alter the expression of genes encoding specific cytokines and chemokines.  Despite the lack of significant regression, however, there was a marked “treatment effect”, characterized by a reduction in tumor cell number and collagen scarring. We attributed these findings to necrosis induced by the direct anti-angiogenic effects of SHP2i. By contrast, the anti-fibrotic effects of SHP2i were reversed in tumors expressing the drug-resistant SHP2.

These data illustrate that tumor genotype (including mutational burden), cell-of-origin/histotype, and intrinsic and extrinsic features of the TME play key roles in the response to targeted therapies, and argue that rational combination therapies must consider all of these effects. Notably, our results differ in detail from other reports [26, 43, 44] that evaluated syngeneic tumor models (e.g., CT26) injected sub-cutaneously, unlike our orthotopic or autochthonous models. Studies combining AMG510 or MTRX849 with targeted or immune therapies, including SHP2is (NCT04330664, NCT04699188, NCT04185883), MEKis (NCT04185883), or anti-PD1(NCT04613596, NCT03785249, NCT04185883) are underway, as is a trial of MRTX849 in combination with the SOS1/pan-KRAS inhibitor BI 1701963 (announced by Boehringer Ingelheim, December 2020). It will be interesting—and important—to determine how these combinations affect the TME as well as the tumor cells themselves, and how well our mouse models predict the human response. Finally, with inhibitors of other mutant KRAS alleles already announced (MRTX1133-KRAS G12D selective inhibitor, Mirati Therapeutics Inc., October 2020 ) or in active development (KRAS-G12D(ON) Inhibitors, Revolution Medicines Inc., September 2020), it will be critical to determine whether the specific mutation also influences the TME response and thus the combination(s) most likely to be optimal for patients.

For further information, contact Dr. Benjamin Neel at benjamin.neel@nyumc.org.

Selected References
  1. Simanshu DK, Nissley DV, McCormick F, 2017. RAS Proteins and Their Regulators in Human Disease. Cell 

    [PubMed Abstract]
  2. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C, 2013. Emerging landscape of oncogenic signatures across human cancers. Nat Genet 

    [PubMed Abstract]
  3. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, Srinivasan P, Gao J, Chakravarty D, Devlin SM, Hellmann MD, Barron DA, Schram AM, Hameed M, Dogan S, Ross DS, Hechtman JF, DeLair DF, Yao J, Mandelker DL, Cheng DT, Chandramohan R, Mohanty AS, Ptashkin RN, Jayakumaran G, Prasad M, Syed MH, Rema AB, Liu ZY, Nafa K, Borsu L, Sadowska J, Casanova J, Bacares R, Kiecka IJ, Razumova A, Son JB, Stewart L, Baldi T, Mullaney KA, Al-Ahmadie H, Vakiani E, Abeshouse AA, Penson AV, Jonsson P, Camacho N, Chang MT, Won HH, Gross BE, Kundra R, Heins ZJ, Chen HW, Phillips S, Zhang H, Wang J, Ochoa A, Wills J, Eubank M, Thomas SB, Gardos SM, Reales DN, Galle J, Durany R, Cambria R, Abida W, Cercek A, Feldman DR, Gounder MM, Hakimi AA, Harding JJ, Iyer G, Janjigian YY, Jordan EJ, Kelly CM, Lowery MA, Morris LGT, Omuro AM, Raj N, Razavi P, Shoushtari AN, Shukla N, Soumerai TE, Varghese AM, Yaeger R, Coleman J, Bochner B, Riely GJ, Saltz LB, Scher HI, Sabbatini PJ, Robson ME, Klimstra DS, Taylor BS, Baselga J, Schultz N, Hyman DM, Arcila ME, Solit DB, Ladanyi M, Berger MF, 2017. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med

    [PubMed Abstract]
  4. Stalnecker CA, Der CJ, 2020. RAS, wanted dead or alive: Advances in targeting RAS mutant cancers. Sci Signal 

    [PubMed Abstract]
  5. Prior IA, Hood FE, Hartley JL, 2020. The Frequency of Ras Mutations in Cancer. Cancer Res

    [PubMed Abstract]
  6. Stephen AG, Esposito D, Bagni RK, McCormick F, 2014. Dragging ras back in the ring. Cancer Cell

    [PubMed Abstract]
  7. Samatar AA, Poulikakos PI, 2014. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov

    [PubMed Abstract]
  8. Wainberg ZA, Alsina M, Soares HP, Braña I, Britten CD, Del Conte G, Ezeh P, Houk B, Kern KA, Leong S, Pathan N, Pierce KJ, Siu LL, Vermette J, Tabernero J, 2017. A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer. Target Oncol

    [PubMed Abstract]
  9. Ryan MB, Corcoran RB, 2018. Therapeutic strategies to target RAS-mutant cancers. Nat Rev Clin Oncol

    [PubMed Abstract]
  10. Hymowitz SG, Malek S, 2018. Targeting the MAPK Pathway in RAS Mutant Cancers. Cold Spring Harb Perspect Med

    [PubMed Abstract]
  11. 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]
  12. Mohi MG, Neel BG, 2007. The role of Shp2 (PTPN11) in cancer. Curr Opin Genet Dev

    [PubMed Abstract]
  13. 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]
  14. Ahmed TA, Adamopoulos C, Karoulia Z, Wu X, Sachidanandam R, Aaronson SA, Poulikakos PI, 2019. SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors. Cell Rep

    [PubMed Abstract]
  15. 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]
  16. Wong GS, Zhou J, Liu JB, Wu Z, Xu X, Li T, Xu D, Schumacher SE, Puschhof J, McFarland J, Zou C, Dulak A, Henderson L, Xu P, O'Day E, Rendak R, Liao WL, Cecchi F, Hembrough T, Schwartz S, Szeto C, Rustgi AK, Wong KK, Diehl JA, Jensen K, Graziano F, Ruzzo A, Fereshetian S, Mertins P, Carr SA, Beroukhim R, Nakamura K, Oki E, Watanabe M, Baba H, Imamura Y, Catenacci D, Bass AJ, 2018.  Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat Med

    [PubMed Abstract]
  17. Mainardi S, Mulero-Sánchez A, Prahallad A, Germano G, Bosma A, Krimpenfort P, Lieftink C, Steinberg JD, de Wit N, Gonçalves-Ribeiro S, Nadal E, Bardelli A, Villanueva A, Bernards R, 2018. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat Med

    [PubMed Abstract]
  18. 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]
  19. Bendell J, Ulahannan S, Koczywas M, Brahmer J, Capasso A, Eckhardt SG, Gordon M, McCoach C, Nagasaka M, Ng K, Pacheco J, Riess J, Spira A, Steuer C, Dua R, Chittivelu S, Masciari S, Wang Z, Wang X, Ou SH, 2020.  Intermittent dosing of RMC-4630, a potent, selective inhibitor of SHP2, combined with the MEK inhibitor cobimetinib, in a phase 1b/2 clinical trial for advanced solid tumors with activating mutations of RAS signaling. Eur J Cancer

  20. Smith MJ, Neel BG, Ikura M, 2013. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A

    [PubMed Abstract]
  21. Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD, 2015. Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. Mol Cancer Res

    [PubMed Abstract]
  22. Fedele C, Li S, Teng KW, Foster CJR, Peng D, Ran H, Mita P, Geer MJ, Hattori T, Koide A, Wang Y, Tang KH, Leinwand J, Wang W, Diskin B, Deng J, Chen T, Dolgalev I, Ozerdem U, Miller G, Koide S, Wong KK, Neel BG, 2021. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med

    [PubMed Abstract]
  23. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM, 2013. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature

    [PubMed Abstract]
  24. Govindan R, Fakih MG, Price TJ, Falchook GS, Desai J, Kuo JC, Strickler JH, Krauss JC, Li BT, Denlinger CS, Durm G, Ngang J, Henary H, Ngarmchamnanrith G, Rasmussen E, Morrow PK, Hong DS, 2019. Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours. Ann Oncol

  25. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, Sudhakar N, Bowcut V, Baer BR, Ballard JA, Burkard MR, Fell JB, Fischer JP, Vigers GP, Xue Y, Gatto S, Fernandez-Banet J, Pavlicek A, Velastagui K, Chao RC, Barton J, Pierobon M, Baldelli E, Patricoin EF 3rd, Cassidy DP, Marx MA, Rybkin II, Johnson ML, Ou SI, Lito P, Papadopoulos KP, Jänne PA, Olson P, Christensen JG, 2020. The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discov

    [PubMed Abstract]
  26. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O'Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR, 2019. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature

    [PubMed Abstract]
  27. Sheridan C, 2020. Grail of RAS cancer drugs within reach. Nat Biotechnol

    [PubMed Abstract]
  28. Ahronian LG, Corcoran RB, 2017. Strategies for monitoring and combating resistance to combination kinase inhibitors for cancer therapy. Genome Med

    [PubMed Abstract]
  29. Konieczkowski DJ, Johannessen CM, Garraway LA, 2018. A Convergence-Based Framework for Cancer Drug Resistance. Cancer Cell

    [PubMed Abstract]
  30. Santana-Codina N, Chandhoke AS, Yu Q, Małachowska B, Kuljanin M, Gikandi A, Stańczak M, Gableske S, Jedrychowski MP, Scott DA, Aguirre AJ, Fendler W, Gray NS, Mancias JD, 2020. Defining and Targeting Adaptations to Oncogenic KRASG12C Inhibition Using Quantitative Temporal Proteomics. Cell Rep

    [PubMed Abstract]
  31. 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]
  32. 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]
  33. 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]
  34. Adachi Y, Ito K, Hayashi Y, Kimura R, Tan TZ, Yamaguchi R, Ebi H, 2020. Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res

    [PubMed Abstract]
  35. Misale S, Fatherree JP, Cortez E, Li C, Bilton S, Timonina D, Myers DT, Lee D, Gomez-Caraballo M, Greenberg M, Nangia V, Greninger P, Egan RK, McClanaghan J, Stein GT, Murchie E, Zarrinkar PP, Janes MR, Li LS, Liu Y, Hata AN, Benes CH, 2019. KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition. Clin Cancer Res

    [PubMed Abstract]
  36. Jänne PA, Rybkin II, Spira AI, Riely GJ, Papadopoulos KP, Sabari JK, Johnson ML, Heist RS, Bazhenova L, Barve M, Pacheco JM, Leal TA, Velastegui K, Cornelius C, Olson P, Christensen JG, Kheoh T, Chao RC, and Ou SHI, 2020. KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Advanced/ Metastatic Non–Small-Cell Lung Cancer (NSCLC) Harboring KRAS G12C Mutation. Eur J Cancer

  37. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchook GS, Price TJ, Sacher A, Denlinger CS, Bang YJ, Dy GK, Krauss JC, Kuboki Y, Kuo JC, Coveler AL, Park K, Kim TW, Barlesi F, Munster PN, Ramalingam SS, Burns TF, Meric-Bernstam F, Henary H, Ngang J, Ngarmchamnanrith G, Kim J, Houk BE, Canon J, Lipford JR, Friberg G, Lito P, Govindan R, Li BT, 2020. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med

    [PubMed Abstract]
  38. Amodio V, Yaeger R, Arcella P, Cancelliere C, Lamba S, Lorenzato A, Arena S, Montone M, Mussolin B, Bian Y, Whaley A, Pinnelli M, Murciano-Goroff YR, Vakiani E, Valeri N, Liao WL, Bhalkikar A, Thyparambil S, Zhao HY, de Stanchina E, Marsoni S, Siena S, Bertotti A, Trusolino L, Li BT, Rosen N, Di Nicolantonio F, Bardelli A, Misale S, 2020. EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. Cancer Discov

    [PubMed Abstract]
  39. 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]
  40. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC, Vonderheide RH, Pittet MJ, Jain RK, Zou W, Howcroft TK, Woodhouse EC, Weinberg RA, Krummel MF, 2018. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med

    [PubMed Abstract]
  41. Quail DF, Joyce JA, 2013. Microenvironmental regulation of tumor progression and metastasis. Nat Med

    [PubMed Abstract]
  42. Niogret C, Birchmeier W, Guarda G, 2019. SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling. Front Immunol

    [PubMed Abstract]
  43. Quintana E, Schulze CJ, Myers DR, Choy TJ, Mordec K, Wildes D, Shifrin NT, Belwafa A, Koltun ES, Gill AL, Singh M, Kelsey S, Goldsmith MA, Nichols R, Smith JAM, 2020. Allosteric Inhibition of SHP2 Stimulates Antitumor Immunity by Transforming the Immunosuppressive Environment. Cancer Res

    [PubMed Abstract]
  44. Wang Y, Mohseni M, Grauel A, Diez JE, Guan W, Liang S, Choi JE, Pu M, Chen D, Laszewski T, Schwartz S, Gu J, Mansur L, Burks T, Brodeur L, Velazquez R, Kovats S, Pant B, Buruzula G, Deng E, Chen JT, Sari-Sarraf F, Dornelas C, Varadarajan M, Yu H, Liu C, Lim J, Hao HX, Jiang X, Malamas A, LaMarche MJ, Geyer FC, McLaughlin M, Costa C, Wagner J, Ruddy D, Jayaraman P, Kirkpatrick ND, Zhang P, Iartchouk O, Aardalen K, Cremasco V, Dranoff G, Engelman JA, Silver S, Wang H, Hastings WD, Goldoni S, 2021. SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms. Sci Rep

    [PubMed Abstract]
< Older Post

RAS-binding compounds: approaching the undruggable from a different perspective

Newer Post >

A Spirit of Scientific Creativity and Excitement: Celebrating the Career of Dr. Jim Hartley

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., “SHP2 Inhibitors for Treating Cancer was originally published by the National Cancer Institute.”

We welcome your comments on this post. All comments must follow our comment policy.

Archive