SOS1 & SHP2 Inhibitors in KRAS NSCLC — PatSnap Eureka
SOS1 & SHP2 Inhibitors in KRAS-Mutant NSCLC: Upstream RAS Suppression Strategies
KRAS mutations drive 25–30% of NSCLC cases. As direct KRAS G12C inhibitors face adaptive resistance, a second wave of innovation targets upstream regulators SOS1 and SHP2—blocking wild-type RAS feedback reactivation and extending therapeutic reach across multiple KRAS alleles.
Why Upstream RAS Suppression Matters in KRAS-Mutant NSCLC
KRAS mutations at codon 12 account for approximately 25% of lung adenocarcinomas, historically representing an "undruggable" oncogenic vulnerability. The clinical advent of direct KRAS G12C inhibitors—sotorasib and adagrasib—has catalyzed a second wave of therapeutic innovation targeting upstream RAS regulators. The core molecular rationale is articulated in multiple retrieved patents: SHP2 activates SOS1, which in turn activates RAS, driving downstream MAPK/ERK signaling and cell proliferation.
Genetic knockdown data from Project DRIVE, cited in a Revolution Medicines filing, demonstrates that PTPN11 (SHP2) knockdown is most closely correlated with SOS1 (correlation coefficient 0.51) and GRB2 (0.4), establishing these as core members of a RAS-regulatory module. This mechanistic linkage underpins the rationale for dual-axis suppression strategies now being patented across the industry. The PatSnap analytics platform enables researchers to map this evolving IP landscape in real time.
SOS1 inhibition is particularly compelling because it is mutation-agnostic—blocking both mutant and wild-type RAS reloading regardless of which KRAS allele is present. A filing from Lupin Limited explicitly notes that SOS1 is essential for 3D spheroid growth of EGFR-mutant NSCLC cells, and that combined EGFR and SOS1 inhibition significantly suppresses Raf/MEK/ERK and PI3K/AKT signaling—signaling broad combinatorial relevance beyond KRAS alone.
Explore the full competitive patent landscape for upstream KRAS inhibition strategies using PatSnap's validated R&D intelligence tools, trusted by leading oncology teams globally.
Four Therapeutic Approaches in the KRAS-Mutant NSCLC Pipeline
Retrieved patent filings and literature describe four distinct modalities targeting the KRAS pathway, from direct covalent inhibitors to upstream GEF and phosphatase blockade.
SOS1 Small-Molecule Inhibitors
SOS1 inhibitors block the SOS1:RAS protein-protein interaction with potent nanomolar IC50 values against SOS1:RAS binding and ERK phosphorylation in cells. The chemical scaffold disclosed by Boehringer Ingelheim covers benzylamine-substituted pyridopyrimidinone compounds (BI-1701963). PatSnap's life sciences intelligence tracks this scaffold's global IP footprint. Mirati Therapeutics filings describe SOS1 inhibitors in combination with adagrasib (MRTX849), noting increased tumor growth inhibition and prolonged disease stabilization relative to KRAS G12C inhibitor monotherapy.
Nanomolar IC50 · Preclinical-to-early-clinical stageSHP2 (PTPN11) Allosteric Inhibitors
The largest volume of retrieved patents covers SHP2 inhibitors, predominantly from Revolution Medicines, Inc. These allosteric inhibitors stabilize the autoinhibited "closed" conformation of SHP2, targeting RAS pathway-driven cancers with KRAS G12C, G12D, G12S, G12V mutations, NF1 loss-of-function, and BRAF class 3 mutations. The lead compound RMC-4630 is explicitly referenced in clinical dosing data. Navire Pharma (BridgeBio) discloses a distinct chemical scaffold (substituted pyrimidinones), signaling competitive IP activity in the PTPN11 space. The NIH recognizes PTPN11 as a validated oncology target.
RMC-4630 · Phase I clinical signal · 14+ jurisdictionsDirect KRAS G12C Covalent Inhibitors (Reference Backbone)
Sotorasib (AMG 510) and adagrasib (MRTX849) are confirmed as the established clinical-stage reference agents. Academic literature confirms adagrasib's Phase II KRYSTAL-1 trial (NCT03785249) results in KRAS G12C-mutant NSCLC patients previously treated with platinum chemotherapy and PD-1/PD-L1 therapy (116 patients, 600 mg twice daily dosing). These agents serve as the backbone upon which upstream combination strategies are being built. The FDA has approved both sotorasib and adagrasib for KRAS G12C-mutant NSCLC.
Sotorasib · Adagrasib · KRYSTAL-1 Phase IIsiRNA Targeting KRAS mRNA
One retrieved patent from Sinobioway Biomedicine Technology (Suzhou) Co., Ltd. discloses siRNA sequences targeting KRAS mRNA—36 siRNA candidates across SEQ ID NOs: 1–74—for KRAS-positive cancers including NSCLC. This represents an early-stage approach distinct from small-molecule inhibitors, positioning nucleic acid therapeutics as a novel modality in the KRAS-mutant NSCLC space. Development stage signals are early preclinical.
36 siRNA candidates · Early preclinical · Novel modalityKey Data Signals from the SOS1 & SHP2 Inhibitor Patent Dataset
Visualised insights derived from patent and literature analysis via PatSnap Eureka across retrieved filings from 2019–2025.
Patent Assignee Activity by Combination Strategy Focus
Revolution Medicines leads SHP2 IP with 14+ jurisdictions; Mirati covers the broadest allele × upstream regulator combination matrix across G12C and G12D.
Combination Strategy Coverage by KRAS Allele & Upstream Target
Eight distinct combination strategies identified across retrieved filings, spanning G12C and G12D alleles with SOS1, SHP2, MEK, and PD-1 co-agents.
Clinical Translation Signals by Compound
RMC-4630 first-in-human dosing at 140–200 mg intermittent schedule; adagrasib KRYSTAL-1 Phase II in 116 patients at 600 mg twice daily.
Project DRIVE: SHP2 Knockdown Genetic Correlations
PTPN11 (SHP2) knockdown is most closely correlated with SOS1 (0.51) and GRB2 (0.4), establishing the core RAS-regulatory module.
Key Patent Holders in the SOS1 & SHP2 Inhibitor Space
Innovation activity is predominantly patent-driven. The following assignees hold the most significant IP positions in this dataset, spanning 2019–2025.
| Assignee | Primary Focus | Key Jurisdictions | Filing Period | Lead Compound |
|---|---|---|---|---|
| Revolution Medicines, Inc. (US) | SHP2 allosteric inhibition; biomarker-stratified selection; SOS1 combinations | WO, CA, AU, SG, BR, CO, MX, KR, IL, IN, JP, TW, RU, US (14+) | 2019–2025 | RMC-4630 |
| Mirati Therapeutics, Inc. (US) | SOS1 + G12C, SOS1 + G12D, SHP2 + G12C, SHP2 + G12D, SOS1 + EGFR | CN, TW, MX, BR | 2021–2025 | MRTX849 (adagrasib) |
| Boehringer Ingelheim GmbH (DE) | SOS1 scaffold originator; SOS1 + G12C; SOS1 + MEK; resistance-focused filings | CL, CN, MX | 2020–2024 | BI-1701963 |
| Novartis AG (CH) | KRAS G12C + SHP2 + PD-1 triple combination (JDQ443 + TNO155 + anti-PD-1) | MX, IL, TW, AU, BR | 2023 | JDQ443 + TNO155 |
Track New Entrants in Real Time
PatSnap Eureka monitors new KRAS-pathway filings across 100+ patent offices globally as they publish.
Five Strategic Implications for the SOS1 & SHP2 Inhibitor Pipeline
Derived from patent signal analysis across retrieved filings. These implications reflect trends observable within this dataset only.
Vertical Pathway Inhibition is the Dominant IP Strategy
The primary commercial logic is dual-axis suppression—direct KRAS allele inhibition (G12C or G12D) combined with upstream node blockade (SOS1 or SHP2)—to preempt adaptive resistance. IP estates are being constructed broadly across KRAS allele × upstream regulator combination matrices, particularly by Mirati Therapeutics and Revolution Medicines. The PatSnap analytics platform enables tracking of this matrix in real time.
SHP2 Has the Deepest Patent Moat in This Dataset
Revolution Medicines has filed in at least 14 jurisdictions on SHP2 inhibitor compositions and methods, with clinical dosing data (RMC-4630) in multiple retrieved filings. Competitors entering the SHP2 space—Navire/BridgeBio, Novartis via TNO155—are differentiating on scaffold chemistry and specific combination claims rather than mechanism novelty.
SOS1 Inhibitors Expanding Beyond G12C into Pan-KRAS Relevance
Boehringer Ingelheim's original G12C-focused SOS1 IP is being complemented by Mirati, Lupin, and Revolution Medicines filings covering SOS1 combinations across G12D, G13C, pan-KRAS, and resistance-to-G12Ci indications. Signals suggest that SOS1 inhibitors may become a backbone agent agnostic of specific KRAS allele—a significant strategic shift from allele-specific to pathway-level intervention.
Resistance to Approved G12C Inhibitors Driving Second-Generation IP
Multiple retrieved filings (Boehringer Ingelheim CN 2024, Revolution Medicines CN 2024) explicitly target patients who have progressed on sotorasib or adagrasib, positioning SOS1 inhibitors and SHP2 inhibitors as rescue agents. This represents a potentially large post-first-line patient population and a distinct commercial positioning opportunity separate from first-line combination use.
Eight Combination Strategies in the Upstream RAS Suppression Pipeline
Retrieved patent filings signal a comprehensive matrix of SOS1 and SHP2 inhibitor combinations spanning multiple KRAS alleles and co-agents. According to WHO global cancer data, lung cancer remains the leading cause of cancer mortality, underscoring the urgency of these resistance-overcoming strategies. The PatSnap life sciences intelligence suite tracks all eight strategy clusters in real time.
SOS1 Inhibitor + KRAS G12C Inhibitor (adagrasib)
Mirati Therapeutics filings (TW, CN, BR) describe synergistic tumor growth inhibition and prolonged disease stabilization in preclinical models. The mechanistic rationale is dual suppression of both mutant KRAS (covalent G12C inhibition) and wild-type RAS reloading (SOS1 blockade of GEF activity).
Mirati · Boehringer Ingelheim · Preclinical synergy confirmedSHP2 Inhibitor + KRAS G12C Inhibitor
Mirati Therapeutics (MX, CN) and Navire Pharma/BridgeBio (BR, TW) both claim this combination, with clinical Phase I signals for RMC-4630 and TNO155. A Mirati CN filing (2021) notes that "RMC-4630 and TNO155 are in Phase I human clinical trials for adult patients with specific advanced solid tumors," citing this as the basis for combining them with KRAS G12C inhibitors.
RMC-4630 · TNO155 · Phase I confirmedSOS1 Inhibitor + KRAS G12D Inhibitor
Mirati Therapeutics (CN, BR, 2024) and Revolution Medicines (CN, 2024) filings address G12D-specific combinations, reflecting extension of the upstream inhibition paradigm beyond G12C to the broader KRAS allele landscape. G12D is prevalent in lung adenocarcinoma (~33% of KRAS-driven cases per the Mirati filing).
Mirati · Revolution Medicines · G12D ~33% of casesSHP2 Inhibitor + KRAS G12D Inhibitor
Mirati Therapeutics (CN, 2024) claims this combination specifically for KRas G12D cancers, indicating parallel IP construction for G12D as an emerging priority allele—mirroring the same dual-axis logic applied to G12C, but now extended to the second-most-prevalent KRAS allele in NSCLC.
Mirati Therapeutics · CN 2024 · G12D priority alleleSOS1 Inhibitor + MEK Inhibitor (incl. G12Ci-resistant tumors)
Boehringer Ingelheim (MX, 2022) claims SOS1 + MEK inhibitor as an anti-cancer combination, and additionally claims this combination for tumors with acquired resistance to KRAS G12C inhibitors (CN, 2024). The resistance-focused filing explicitly acknowledges that acquired resistance to sotorasib and adagrasib is anticipated to involve secondary KRAS mutations.
Boehringer Ingelheim · Resistance rescue strategy · CN 2024KRAS G12C + SHP2 + PD-1 Inhibitor (Triple Combination)
Novartis AG (IL, TW, BR, AU) filings describe a triple combination of JDQ443 (KRAS G12C inhibitor) + TNO155 (SHP2 inhibitor) + PD-1 inhibitor, representing an emerging multi-modal immuno-oncology and targeted therapy approach. This is among the most complex combination strategies in the retrieved dataset. The PatSnap Trust Center ensures enterprise-grade data security for sensitive pipeline intelligence.
Novartis · JDQ443 + TNO155 + PD-1 · Multi-modal IOSOS1 & SHP2 Inhibitors in KRAS NSCLC — key questions answered
KRAS mutations drive approximately 25–30% of non-small cell lung cancer (NSCLC) cases. Among NSCLC cases, KRAS mutations at codon 12 account for approximately 25% of lung adenocarcinomas, with G12C representing the most prevalent single substitution (~40% of all KRAS-mutant NSCLC), followed by G12D and G12V.
SOS1 is positioned upstream of all RAS isoforms, making SOS1 inhibition mutation-agnostic—a critical advantage over allele-specific KRAS inhibitors such as sotorasib or adagrasib which target only KRAS G12C. SOS1 inhibition blocks both mutant and wild-type RAS reloading, offering broader coverage across KRAS alleles including G12D, G12V, and G13C.
SHP2 (encoded by PTPN11) is an allosteric protein tyrosine phosphatase positioned upstream of RAS, activated by receptor tyrosine kinases. Allosteric SHP2 inhibitors work by stabilizing the autoinhibited "closed" conformation of SHP2, preventing RTK-mediated reactivation of wild-type RAS via the SHP2→SOS1→RAS axis. Revolution Medicines describes a biomarker-informed approach using SHP2 phosphorylation state at Y542 (but not Y580) to determine target engagement.
Revolution Medicines, Inc. is the most prolific SHP2 inhibitor patent holder in this dataset, with filings across at least 14 jurisdictions (WO, CA, AU, SG, BR, CO, MX, KR, IL, IN, JP, TW, RU, US). Boehringer Ingelheim International GmbH is the originator of the pyridopyrimidinone SOS1 inhibitor scaffold (BI-1701963). Mirati Therapeutics, Inc. is active across SOS1 + KRAS G12C, SOS1 + KRAS G12D, SHP2 + KRAS G12C, and SHP2 + KRAS G12D combination filings. Lupin Limited and Navire Pharma/BridgeBio are also active filers.
The Revolution Medicines CN patent filing on SHP2 inhibitor dosing (2022) explicitly describes a first-in-human study design with dose levels of 20, 40, 60, and 80 mg (single dose) and intermittent schedules of 140 or 200 mg (D1 or D4 of 7-day cycles). Plasma concentrations are reported to exceed pERK EC50 for KRAS G12C tumors under intermittent dosing. Preclinical data shows tumor regression in KRAS G12C NSCLC mouse models at 10–30 mg/kg daily dosing.
Novartis AG filings describe a triple combination of JDQ443 (KRAS G12C inhibitor) + TNO155 (SHP2 inhibitor) + PD-1 inhibitor, representing an emerging multi-modal immuno-oncology and targeted therapy approach. The rationale is that combining direct KRAS allele inhibition with upstream SHP2 blockade to prevent wild-type RAS reactivation, plus immune checkpoint inhibition, may achieve more durable responses than any doublet alone.
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References
- Anti-cancer combination therapy comprising SOS1 inhibitor and KRAS G12C inhibitor — Boehringer Ingelheim International GmbH, 2023, CN [Patent]
- Benzylamine-substituted pyridopyrimidinone compounds and derivatives, SOS1 inhibitors — Boehringer Ingelheim International GmbH, 2020, CL [Patent]
- Anticancer combination therapy (SOS1 inhibitor + MEK inhibitor) — Boehringer Ingelheim International GmbH, 2022, MX [Patent]
- Anti-cancer therapy (SOS1 and/or MEK inhibitor for KRAS G12C inhibitor-resistant cancers) — Boehringer Ingelheim International GmbH, 2024, CN [Patent]
- SHP2 inhibitor compositions and methods for treating cancer (WO, foundational) — Revolution Medicines, Inc., 2019, WO [Patent]
- SHP2 inhibitor compositions and methods for treating cancer (CA, Project DRIVE SOS1 correlation data) — Revolution Medicines, Inc., 2019, CA [Patent]
- SHP2 inhibitor dosing and methods of treating cancer (RMC-4630 clinical dosing, intermittent schedule) — Revolution Medicines, Inc., 2022, IL [Patent]
- SHP2 inhibitor dosing and methods of treating cancer (RMC-4630 first-in-human) — Revolution Medicines Inc. (Rui Xin Pharmaceutical), 2022, CN [Patent]
- SHP2 inhibitor compositions and methods for treating cancer (biomarker Y542 phosphorylation, KRAS G12C xenograft) — Revolution Medicines, Inc., 2020, SG [Patent]
- Use of SOS1 inhibitors to treat malignancies with SHP2 mutations — Revolution Medicines, Inc., 2023, MX [Patent]
- Using SOS1 inhibitors and RAS inhibitors to treat cancer — Revolution Medicines Inc. (Rui Xin Pharmaceutical), 2024, CN [Patent]
- Combination therapies (SOS1 inhibitor + KRas G12C inhibitor adagrasib, TW) — Mirati Therapeutics, Inc., 2023, TW [Patent]
- Combination therapies (SOS1 inhibitor + KRas G12C inhibitor, CN, tumor growth inhibition data) — Mirati Therapeutics, Inc., 2024, CN [Patent]
- Combination therapies of KRAS G12D inhibitors with SOS1 inhibitors (BR) — Mirati Therapeutics, Inc., 2024, BR [Patent]
- KRAS G12D inhibitor and SOS1 inhibitor combination therapy (CN) — Mirati Therapeutics, Inc., 2024, CN [Patent]
- KRAS G12D inhibitor and SHP2 inhibitor combination therapy (CN) — Mirati Therapeutics, Inc., 2024, CN [Patent]
- Combination therapies (SHP-2 inhibitor + KRAS G12C inhibitor, MX) — Mirati Therapeutics, Inc., 2021, MX [Patent]
- Combination therapies (SOS1 + EGFR inhibitor) — Mirati Therapeutics, Inc., 2025, BR [Patent]
- Pharmaceutical combinations comprising a KRAS G12C inhibitor (JDQ443) + SHP2 inhibitor (TNO155) + PD-1 inhibitor (IL) — Novartis AG, 2023, IL [Patent]
- Pharmaceutical combinations comprising a KRAS G12C inhibitor and uses thereof for the treatment of cancers (AU) — Novartis AG, 2023, AU [Patent]
- Combination therapy using a PTPN11 inhibitor and a G12C inhibitor in KRAS — Navire Pharma, Inc., 2024, BR [Patent]
- Combination therapy using a PTPN11 inhibitor and a KRAS G12C inhibitor (TW) — BridgeBio Services Inc., 2023, TW [Patent]
- Pharmaceutical combinations of SOS1 inhibitors to treat and/or prevent cancer (BR) — Lupin Limited, 2023, BR [Patent]
- Pharmaceutical combinations of SOS1 inhibitors for treating and/or preventing cancer (IL) — Lupin Limited, 2023, IL [Patent]
- Adagrasib: A landmark in the KRASG12C-mutated NSCLC — Jie He and Zhenlin Yang, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, 2022 [Paper]
- siRNA targeting KRAS gene and its application in preparing drugs for KRAS-positive cancer treatment — Sinobioway Biomedicine Technology (Suzhou) Co., Ltd., 2024, CN [Patent]
- National Cancer Institute — KRAS gene and lung cancer [External reference]
- National Institutes of Health — PTPN11/SHP2 as oncology target [External reference]
- U.S. Food and Drug Administration — Sotorasib and adagrasib approvals for KRAS G12C NSCLC [External reference]
- World Health Organization — Global cancer statistics and lung cancer mortality [External reference]
All data and statistics on this page are sourced from the references above and from PatSnap's proprietary innovation intelligence platform. This page represents a snapshot of innovation signals within a targeted patent and literature dataset only and should not be interpreted as a comprehensive view of the full clinical pipeline or regulatory landscape.
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