Combined KRAS<sup>G12C</sup>and SOS1 inhibition enhances and extends the anti-tumor response in KRAS<sup>G12C</sup>-driven cancers by addressing intrinsic and acquired resistance

Thatikonda, Venu; Lu, Hengyu; Jurado, Sabine; Kostyrko, Kaja; Bristow, Christopher A.; Bosch, Karin; Feng, Ningping; Gao, Shuwei; Gerlach, Daniel; Gerlach, Michael; Lieb, Simone; Jeschko, Astrid; Machado, Annette A.; Marszalek, Ethan D.; Mahendra, Mikhila; Jaeger, Philipp A.; Sorokin, Alexey V.; Strauss, Sandra J.; Trapani, Francesca; Kopetz, Scott; Vellano, Christopher P.; Petronczki, Mark; Kraut, Norbert; Heffernan, Timothy P.; Marszalek, Joseph R.; Pearson, Mark; Waizenegger, Irene C.; Hofmann, Marco H.

doi:10.1101/2023.01.23.525210

Cited by 15 publications

(13 citation statements)

References 67 publications

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“…In addition to SOS2 KO, inhibition of proximal RTK signaling via the SHP2 inhibitors RMC-4550 or SHP099 significantly inhibited osimertinib resistance in EGFR -mutated LUAD cells ( 30 ). The SOS1 inhibitor BI-3406 significantly inhibited acquired resistance to the KRAS G12C ( 71 ) or MEK ( 72 ) inhibitors in KRAS G12 -mutatated LUAD cells. Based on these data, we propose that inhibition of proximal RTK signaling could be a common mechanism to prevent resistance to targeted therapies in a majority of LUAD.…”

Section: Discussionmentioning

confidence: 99%

SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

Theard

Linke

Sealover

et al. 2023

Preprint

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Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2 KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2 KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long term in situ resistance model, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2 KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiary EGFR mutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting

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Section: Discussionmentioning

confidence: 99%

SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

Theard

Linke

Sealover

et al. 2023

Preprint

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“…SOS2 KO enhanced the efficacy of osimertinib‐dependent inhibition of oncogenic (3D) growth and reduced the development of acquired osimertinib resistance by limiting RTK/PI3K pathway reactivation. These results, in conjunction with studies assessing SHP2 [54] and SOS1 [29,110] inhibitors as secondary therapeutics in EGFR ‐ and KRAS ‐mutate LUAD, suggest that inhibiting proximal RTK signaling may be a common secondary therapeutic strategy to enhance outcomes for patients with RTK/RAS pathway mutated lung adenocarcinomas.…”

Section: Discussionmentioning

confidence: 92%

“…In addition to SOS2 KO , inhibition of proximal RTK signaling via the SHP2 inhibitors RMC‐4550 or SHP099 significantly inhibited osimertinib resistance in EGFR ‐mutated LUAD cells [54]. The SOS1 inhibitor BI‐3406 significantly inhibited acquired resistance to KRAS G12C inhibitors [110] or MEK inhibitors [29] in KRAS G12 ‐mutated LUAD cells. Based on these data, we propose that inhibition of proximal RTK signaling could be a common mechanism to prevent resistance to targeted therapies in a majority of LUAD.…”

Section: Discussionmentioning

confidence: 99%

“…Although SOS1 and SOS2 were previously considered poor candidates for therapeutic intervention due to their low oncogenic potential, recent studies showed that both SOS1 and SOS2 may be important therapeutic targets in EGFR-and KRAS-mutated cancers [21][22][23][24][25][26][27]. While there are currently no SOS2 inhibitors, SOS1 inhibitors BAY-293 and BI-3406 show strong synergy with EGFR-TKIs [24,27], KRAS G12C [21,28], and MEK [22,29,30] inhibitors to inhibit survival of EGFR-or KRAS-mutated LUAD cells [4]. Based on these studies, SOS1 inhibitors are currently in Phase I/II trials for treating KRAS-mutated cancers both as a single agent and in combination with KRAS G12C [NCT04185883; NCT04975256; NCT05578092] or MEK [NCT04111458] inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…SOS1 and SOS2 further have differential effects on activation of RAF/MEK/ERK versus PI3K/AKT effector pathways. SOS1 is a critical regulator of RAF/MEK/ERK signaling in both physiologic [33,38,39,41,43] and oncogenic [21,22,24,[27][28][29]34,51] settings. In contrast, SOS2 regulates RTK-PI3K signaling to regulate survival of both epidermal stem cell survival [32] and KRAS-mutated cancer cells [25,26].…”

Section: Introductionmentioning

confidence: 99%

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SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma

Theard,

Linke,

Sealover

et al. 2024

Molecular Oncology

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Son of sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic receptor tyrosine kinase (RTK)‐dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR tyrosine kinase inhibitor (EGFR‐TKI) osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion (SOS2KO) sensitized EGFR‐mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit phosphatidylinositol 3‐kinase (PI3K)/AKT pathway activation, oncogenic transformation, and survival. Bypassing RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR‐TKIs; SOS2KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET‐driven bypass model, SOS2KO inhibited hepatocyte growth factor (HGF)‐stimulated PI3K signaling to block HGF‐driven osimertinib resistance. Using a long‐term in situ resistance assay, most osimertinib‐resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT‐dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2KO cultures that became osimertinib resistant primarily underwent non‐RTK‐dependent epithelial–mesenchymal transition (EMT). Since bypassing RTK reactivation and/or tertiary EGFR mutations represent most osimertinib‐resistant cancers, these data suggest that targeting proximal RTK signaling, here exemplified by SOS2 deletion, has the potential to delay the development osimertinib resistance and enhance overall clinical responses for patients with EGFR‐mutated LUAD.

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Identifying Potential SOS1 Inhibitors via Virtual Screening of Multiple Small Molecule Libraries against KRAS‐SOS1 Interaction

Ikram,

Sayyah,

Durdağı

2024

ChemBioChem

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The RAS‐MAPK signaling pathway, crucial for cell proliferation and differentiation, involves key proteins KRAS and SOS1. Mutations in the KRAS and SOS1 genes are implicated in various cancer types, including pancreatic, lung, and juvenile myelomonocytic leukemia. There is considerable interest in identifying inhibitors targeting KRAS and SOS1 to explore potential therapeutic strategies for cancer treatment. In this study, advanced in silico techniques were employed to screen small molecule libraries at this interface, leading to the identification of promising lead compounds as potential SOS1 inhibitors. Comparative analysis of the average binding free energies of these predicted potent compounds with known SOS1 small molecule inhibitors revealed that the identified compounds display similar or even superior predicted binding affinities compared to the known inhibitors. These findings offer valuable insights into the potential of these compounds as candidates for further development as effective anti‐cancer agents.

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Combined KRAS^G12Cand SOS1 inhibition enhances and extends the anti-tumor response in KRAS^G12C-driven cancers by addressing intrinsic and acquired resistance

Cited by 15 publications

References 67 publications

SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma

Identifying Potential SOS1 Inhibitors via Virtual Screening of Multiple Small Molecule Libraries against KRAS‐SOS1 Interaction

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Combined KRASG12Cand SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

Cited by 15 publications

References 67 publications

SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma

Identifying Potential SOS1 Inhibitors via Virtual Screening of Multiple Small Molecule Libraries against KRAS‐SOS1 Interaction

Contact Info

Product

Resources

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Combined KRAS^G12Cand SOS1 inhibition enhances and extends the anti-tumor response in KRAS^G12C-driven cancers by addressing intrinsic and acquired resistance