Targeting SHP2: Dual breakthroughs in colorectal cancer therapy–from signaling pathway modulation to immune microenvironment remodeling

Abstract

SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer (CRC) progression, and it is consistently overexpressed in CRC. It facilitates CRC oncogenesis by mediating downstream signaling cascades of receptor tyrosine kinases, including the RAS/ERK, JAK/STAT, and PI3K/AKT pathways, which are clinically associated with poor prognosis. Furthermore, SHP2 orchestrates immunosuppressive signaling networks by impairing cytotoxic T cell infiltration and changing the phenotype of tumor-associated macrophages within the tumor microenvironment (TME). Targeting SHP2 represents a dual therapeutic strategy in CRC: It concurrently regulates RTK signaling and reprograms the immunosuppressive TME. SHP2 inhibitors, administered both as monotherapy and in combination regimens, have advanced into clinical trial phases. Consequently, SHP2 serves as both a molecular target for precision oncology and an immunomodulatory node, positioning it as a high-priority candidate for CRC treatment.

Key Words: Colorectal cancer; Protein tyrosine phosphatase SHP2; Targeted therapy; PI3K/AKT pathway; Tumor microenvironment

Core Tip: This paper summarizes the regulatory mechanisms of SHP2 in colorectal cancer (CRC) and emerging therapeutic strategies targeting SHP2. The findings demonstrated that SHP2 serves as a master oncogenic regulator in CRC pathogenesis by coordinating receptor tyrosine phosphatase-mediated signaling. Notably, SHP2 remodels the tumor immune microenvironment by modulating macrophage and T cell functions. Allosteric SHP2 inhibitors, which are characterized by high oral bioavailability and potent target specificity, are currently under evaluation in multicenter phase I/II trials. Although acquired resistance remains challenging, combination strategies, particularly immunotherapy-based treatments, have shown transformative potential, accelerating the transition of SHP2-targeted therapies and offering novel paradigms for personalized CRC treatment.

INTRODUCTION

Colorectal cancer (CRC) is a prevalent malignant tumor within the gastrointestinal tract and has emerged as a growing global health challenge[1,2]. With an increasing emphasis on physical examinations, the detection rate of CRC has risen annually. According to the latest epidemiological data, CRC accounts for 9.6% of incident malignancies (third most prevalent) and 9.3% of global cancer mortalities (second leading cause)[1,3]. Although recent therapeutic advancements have significantly improved survival outcomes in CRC, the 5-year survival rate for metastatic CRC is lower than 15%, underscoring the urgent need to elucidate its molecular mechanisms and identify novel therapeutic targets[4,5].

Protein tyrosine phosphorylation, a critical post-translational modification, regulates cellular signaling networks through the dynamic balance between protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs)[6-8]. Dysregulation of protein tyrosine phosphorylation is a key driver of oncogenesis across multiple cancer lineages[9]. There is a striking disparity in the current pharmacological landscape; namely, many PTK inhibitors have been approved for clinical tumor treatment, whereas PTP-targeted drugs remain in the exploratory phase[10,11]. Notably, SHP2, encoded by the PTPN11 gene, is the first validated proto-oncogenic phosphatase[12]. SHP2 manifests dual oncogenic functionality in colorectal carcinogenesis, as it drives tumor progression via classical pathways such as PI3K/AKT and RAS/MAPK signaling and plays a crucial role in immune microenvironment remodeling. This paper reviews the molecular mechanisms of SHP2 in CRC and its translational potential for clinical treatment.

STRUCTURAL FEATURES OF SHP2

SHP2 is a non-receptor protein tyrosine phosphatase (PTP) characterized by three domains: tandem N-terminal SH2 domains (N-SH2 and C-SH2) and a C-terminal catalytic (PTP) domain, as well as a regulatory tail containing tyrosine phosphorylation sites (Y542/Y580)[13,14]. In the resting state, SHP2 is auto-inhibited through interactions between N-SH2 and the PTP domain, which suppress the catalytic activity of SHP2[15]. Ligand-induced activation of RTKs triggers phosphorylation of specific intracellular tyrosine residues, which bind to the SH2 domain, inducing conformational changes to expose the catalytic site of SHP2. Importantly, phosphorylation at Y542/Y580 simultaneously releases the self-inhibitory state and activates the downstream signaling cascade by recruiting the adaptor protein Grb2[16,17].

REGULATORY MECHANISMS OF SHP2 IN CRC

Expression characteristics and clinical prognosis

Although early studies reported SHP2 downregulation in the cancer tissues of patients with CRC compared to normal adjacent tissues, recent large-scale cohort studies revealed that SHP2 expression is significantly higher in CRC tissues than in adjacent mucosal tissues, and its elevated expression is significantly associated with improved prognosis[18-20]. This dysregulation was also observed in sporadic colorectal adenomas, in which SHP2 was upregulated in hyperplastic epithelial compartments[21]. Significantly elevated SHP2 phosphorylation has also been observed in CRC tissues compared to non-neoplastic controls[22]. Clinicopathological correlation analysis demonstrated that decreased SHP2 expression is significantly associated with poor differentiation, lymph node metastasis, and advanced TNM stage, suggesting its potential as an independent prognostic biomarker of CRC[18,20].

Core signaling pathway regulation

SHP2 plays a dual regulatory role in the PI3K/AKT pathway in CRC. SHP2 depletion in CRC cells demonstrates potent antitumor effects through dual suppression of cellular proliferation and induction of apoptosis[23]. It exerts its oncogenic activity via PI3K/AKT pathway activation; SHP2 is upregulated in oxaliplatin-resistant cells, where it drives chemoresistance via AKT hyperphosphorylation[23]. SHP2 plays a critical role in the ferroptosis regulatory network, as it orchestrates the PI3K/BRD4/TFEB axis to inhibit ferritinophagy, thereby attenuating ROS generation and blocking iron-dependent cell death mechanisms essential for tumor survival[24]. Concurrently, SHP2 promotes metastatic progression through Tie2-PI3K/AKT/mTOR-mediated vascular remodeling. Genetic ablation of SHP2 paradoxically amplifies Ang/Tie2-PI3K signaling, upregulating vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) to potentiate hepatic metastasis[25]. Intriguingly, the regulatory role of SHP2 in PI3K signaling exhibits pathological context-dependence: in diabetes-associated CRC, SHP2 knockdown attenuates PI3K/AKT phosphorylation but augments tumor cell invasiveness, implying metabolic reprogramming rewires SHP2-PI3K crosstalk[26]. Therapeutic challenges emerge from compensatory AKT reactivation through PDGFRβ-PI3K signaling during SHP2 monotherapy, which can be circumvented by SHP2 inhibitors and AKT/FAK inhibitors in combination to achieve synergistic pathway blockade[22]. Resistance mechanisms involve WWP1-mediated AKT resilience, effectively addressed through dual SHP2/WWP1 inhibition using agents like I3C[27]. Emerging therapeutic agents, such as metallocene-curcumin hybrid derivatives (e.g., compound 3f), show dual efficacy by directly suppressing PI3K-AKT signaling while modulating tumor immune microenvironment, highlighting the multifaceted potential of the SHP2-PI3K axis modulation in precision CRC therapeutics[28]. This bidirectional regulation highlights the therapeutic complexity of targeting SHP2 in CRC, especially in comorbid metabolic disorders (Figure 1).

Figure 1 SHP2 plays a dual regulatory role in the PI3K/AKT pathway. SHP2 activates the PI3K/AKT pathway, contributing to chemoresistance. SHP2 decreases ROS production and inhibits ferroptosis via the PI3K/BRD4/TFEB axis. SHP2 stimulates the Tie2-PI3K/AKT/mTOR signaling cascade to mediate vascular remodeling and colorectal cancer (CRC) metastasis. In diabetes-associated CRC, SHP2 knockdown suppresses PI3K-AKT phosphorylation, enhances invasiveness. Monotherapy targeting SHP2 triggers feedback activation of AKT, necessitating its combination with AKT inhibitors for effective blockade. SHP2 inhibitors suppress the PI3K/AKT pathway and cell proliferation. CRC: Colorectal cancer. Created with biogdp.com (Supplementary material).

SHP2 expression exhibited a negative correlation with nuclear STAT3 expression in CRC, a marker of the JAK/STAT pathway. Patients with elevated SHP2 expression and diminished nuclear STAT3 levels experienced significantly longer disease-specific survival and disease-free survival[29]. TRIM52 deletion decreased STAT3 phosphorylation and increased SHP2 expression, thereby inhibiting cell proliferation and tumor growth[30]. SHP2 inhibited CRC cell proliferation by dephosphorylating STAT3 at Tyr705, whereas mutant-p53 reversed this suppression via competitive binding to STAT3[29-31]. Additionally, interactions between SHP2 and IL22R1 activate STAT3, thereby stimulating the JAK/STAT pathway and promoting cell proliferation[32]. Consequently, the regulation of STAT3 by SHP2 is pathway-specific (Figure 2).

Figure 2 SHP2 regulates the STAT3 pathway. SHP2 negatively regulates STAT3 in colorectal cancer, correlating with improved disease-specific survival and disease-free survival. TRIM52 deletion suppresses STAT3 phosphorylation via SHP2 upregulation, inhibiting tumor growth. SHP2 dephosphorylates STAT3 to block proliferation, while mutant p53 competitively binds to STAT3 to reverse this suppression. Paradoxically, the SHP2-IL22R1 interaction activates STAT3-mediated JAK/STAT signaling, driving proliferation. Created with biogdp.com (Supplementary material).

In the RAS/MAPK pathway, SHP2-IL-22R1 binding is essential for IL-22–mediated ERK activation, which drove downstream MAPK signaling to promote cell proliferation[32]. MUC1-C interacted with SHP2 to enhance RTK-mediated RAS/ERK signaling, making it a potential therapeutic target in BRAF^V600E-mutant CRC[33]. Moreover, SHP2 deletion in KRAS-mutant CRC cells significantly reduced RAF/MEK/ERK phosphorylation, resulting in marked impairment of proliferation and invasive capacity[21]. In addition, treatment with the SHP2 allosteric inhibitor PCC0208023 suppressed KRAS-mutated CRC cell proliferation through RAS/MAPK pathway blockade and demonstrated potent antitumor efficacy in preclinical models[34] (Figure 3).

Figure 3 SHP2 modulates the RAS/ERK pathway. SHP2 binding to IL-22R1 activates ERK signaling, thereby facilitating MAPK signaling and promoting cell proliferation. MUC1-C interacts with SHP2, enhancing RTK-RAS/ERK signaling, thus making it a promising therapeutic target for BRAF^V600E-mutant CRC. SHP2 deficiency diminishes RAF/MEK/ERK phosphorylation in KRAS-mutant CRC cells. The SHP2 inhibitor PCC0208023 suppresses cell proliferation by inhibiting the RAS/MAPK pathway and exhibits tumor volume reduction in preclinical models. CRC: Colorectal cancer. Created with biogdp.com (Supplementary material).

Tumor microenvironment remodeling

SHP2 has emerged as a critical regulator of the tumor microenvironment (TME) in CRC. In tumor-associated macrophages (TAMs), targeting SHP2 with PHPS1 attenuates its expression in macrophages, which activates the PI3K/AKT pathway to induce M2-polarized TAMs and exosome secretion, ultimately fostering CRC metastasis. Pharmacological blockade of PI3K by LY294002 reverses this pro-metastatic phenotype[35]. SHP2 deficiency in TAMs also biases macrophages toward M2 polarization through STAT3 activation and NF-κB inhibition, as evidenced by reduced pro-inflammatory cytokine secretion and elevated MMP levels[36]. Genetic ablation of SHP2 in macrophages exacerbates CRC hepatic metastasis through the Tie2-PI3K/AKT/mTOR signaling axis. This aberrant signaling cascade transcriptionally upregulates pro-metastatic mediators, including VEGF (angiogenesis), COX-2 (prostaglandin synthesis), and MMP2/MMP9 (extracellular matrix remodeling), collectively fostering a metastasis-permissive niche through dual modulation of angiogenic switching and stromal reorganization[25]. However, SHP2 deletion in TAMs was also reported to protect mice from colitis-associated colorectal carcinogenesis[37]. Strikingly, myeloid-specific SHP2 ablation activated the STING/TBK1/IRF3 pathway and enhanced type I interferon production, thus promoting CD8⁺ T cell infiltration and delaying tumor progression by reprogramming the immunosuppressive CRC TME[38].

CD4⁺ T cell-specific SHP2 deficiency resulted in a reduced tumor volume, accompanied by elevated IFN-γ expression and amplified cytotoxic CD8⁺ T cell activity[39]. Mice with T cell-specific deletion of SHP2 demonstrated slowed tumor growth. Moreover, inhibition of SHP2 using the allosteric inhibitor SHP099 potentiated antitumor immunity, as evidenced by STAT1 hyperphosphorylation, an elevated proportion of CD8⁺IFN-γ⁺ T cells and a marked reduction in tumor burden, underscoring its therapeutic potential in remodeling the CRC TME[40] (Figure 4).

Figure 4 SHP2 regulates the colorectal cancer tumor microenvironment. SHP2 regulates the PI3K/AKT, JAK/STAT, and RAS/ERK pathways to mediate tumor cell proliferation, drug resistance, and tumor growth. In tumor-associated macrophages (TAMs), SHP2 mediates cytokine release, angiogenesis, and tumor microenvironment remodeling through PI3K/AKT, NF-κB, and STAT3 signaling pathways, leading to colorectal cancer metastasis. In T cells, SHP2 primarily participates in tumor microenvironment remodeling and mediates tumor suppression through the STAT1 and IFN-γ pathways. VEGF: Vascular endothelial growth factor; MMP: Matrix metalloproteinase. Created with biogdp.com (Supplementary material).

TRANSLATIONAL DEVELOPMENT OF SHP2 INHIBITORS

Limitations of monotherapy

Therapeutic targeting of SHP2 in CRC has entered a transformative phase, marked by a growing number of inhibitors progressing through preclinical development and clinical trials, including TNO155 (NCT03114319, NCT04000529), RMC-4630 (NCT03634982), ET0038(NCT05354843), BBP-398(NCT04528836), JAB-3312 (NCT04121286), and JAB-3068 (NCT03518554, NCT03565003; Table 1). These agents abolish downstream signaling of SHP2 by binding to the PTP or SH2 domain, thereby suppressing enzymatic activity or preventing substrate interactions[41,42]. Notably, TNO155 represents a new paradigm for allosteric inhibitors, as it demonstrated high selectivity for the allosteric pocket within the PTP domain. This mechanism effectively disrupts both the catalytic activity and substrate recruitment capacity of SHP2. Preclinical studies validated its antitumor efficacy and favorable pharmacokinetic data in tumor cell lines and mouse models[43-45]. Meanwhile, other inhibitors such as RMC-4630 exhibited similar antiproliferative effects in CRC preclinical models, underscoring the therapeutic potential of SHP2 inhibition in CRC.

Table 1 Clinical trials targeting SHP2.

Trial name (NCT number)	Phase	Combination/therapeutic strategy	Target indication	Key populations/findings	Status/updates
NCT03634982	Phase 1	RMC-4630	Advanced solid tumors (including CRC)	Monotherapy	Active
NCT04121286	Phase 1	JAB-3312	Advanced solid tumors (including CRC)	Monotherapy	Recruiting
NCT03518554*	Phase 1	JAB-3068	Advanced solid tumors (including CRC)	Monotherapy	Complete
NCT03565003	Phase 1/2	JAB-3068	Advanced solid tumors (including CRC)	Monotherapy	Complete
NCT05354843	Phase 1	ET0038	Advanced solid tumors (including CRC)	Monotherapy	Recruiting
NCT04528836	Phase 1	BBP-398	Advanced solid tumors (including CRC)	Monotherapy	Terminated in 2024
NCT03114319	Phase 1	TNO155 + nazartinib	Advanced EGFR/KRAS-mutant solid tumors	Monotherapy or combination use with EGFR TKIs	Active
NCT04330664	Phase 1	TNO155 + MRTX849	Advanced solid tumors with KRASG12C mutation	Combination therapy	Complete
NCT04294160	Phase 1	Dabrafenib + LTT462 + TNO155 Dabrafenib + trametinib + TNO155	Advanced or metastatic BRAFV600E-mutated CRC	Combination therapy	Terminated in 2024
NCT04000529	Phase 1	TNO155 + spartalizumab/ribociclib	Selected malignancies	Monotherapy or combination of TNO155 with spartalizumab or with ribociclib	Terminated in 2024
NCT04699188	Phase 1/2	JDQ443 + TNO155 + tislelizumab	KRASG12C-mutant NSCLC, CRC	Monotherapy or with KRASG12C inhibitor, Dose Escalation Study	Active
NCT04916236	Phase 1	RMC-4630 + LY3214996	Metastatic KRAS-mutant CRC, PDAC, and NSCLC	Combination therapy of RMC-4630 (SHP2 inhibitor) and LY3214996 (ERK inhibitor)	Terminated in 2024
NCT04185883	Phase 1	Sotorasib + RMC-4630	KRASG12C mutant advanced solid tumors	Combination therapy	Recruiting
NCT04670679	Phase 1	ERAS-601 + cetuximab/pembrolizumab	Advanced solid tumors (including CRC)	Monotherapy or combination treatment with cetuximab/pembrolizumab	Active
NCT04252339	Phase 1	RLY-1971	Advanced or metastatic solid tumors	Monotherapy, dose escalation, and expansion study	Complete

NCT: National clinical trial; CRC: Colorectal cancer.

However, emerging clinical data also suggest the emergence of an acquired resistance mechanism in patients treated with SHP2 inhibitors. Certain SHP2 mutations (e.g., G503V) conferred resistance to SHP2 inhibitors[46]. Additionally, rapid feedback-induced re-activation of AKT signaling following SHP2 inhibition emerged as a dominant resistance mechanism in CRC[22]. Recent studies identified a phenyl urea compound as a novel SHP2 inhibitor, with the compound exerting dual therapeutic effects through potent antiproliferative effects against SHP099/TNO155-resistant tumor cells and by reversing PD-L1–mediated immunosuppression. This compound significantly suppressed tumor growth in murine models, offering new insights into SHP2-mediated therapeutic resistance[45].

Combinatorial therapeutic strategies

Current combination strategies for CRC treatment are primarily classified into three categories: chemotherapy sensitization, targeted synergy, and immunotherapy. The combined use of SHP2 inhibitors with regorafenib or celastrol led to markedly enhanced therapeutic efficacy in CRC, as evidenced by reduced tumor size, decreased cell proliferation, increased apoptosis, and elevated antitumor immune responses in vivo[44,47]. Furthermore, the combined administration of TNO155 and CDK4/6 inhibitors resulted in superior tumor growth inhibition in patient-derived xenograft models of CRC[48]. Synergistic antitumor effects were also observed upon combining SHP2 inhibitors with EGFR/MEK inhibitors[49].

Notably, the combination of allosteric SHP2 inhibitors and immune checkpoint inhibitors re-sensitized immunotherapy-resistant CRC to immune checkpoint blockade. The combination of SHP099 and anti-PD-1 antibodies achieved significantly higher efficacy in suppressing tumor growth compared to monotherapy[40,46]. Moreover, neddylation-mediated SHP2 inactivation in macrophages increased phagocytosis, thereby substantially enhancing the outcomes of CRC immunotherapy[50].

Ongoing clinical trials are evaluating SHP2 inhibitor-based combination therapies, such as TNO155 (NCT04294160, NCT04330664, NCT04699188) and RMC-4630 (NCT04916236), in molecularly stratified patients, aiming to advance precision oncology strategies for CRC (Table 1).

CONCLUSION

SHP2 is emerging as an oncogenic driver across malignancies, such as lung cancer, CRC, breast cancer, liver cancer, melanoma, pancreatic cancer and acute myeloid leukemia[20,41,51]. As SHP2 inhibitors (e.g., RMC-4630, TNO155) have begun to show clinical efficacy in diverse malignancies, SHP2 represents the first phosphatase-targeted agent achieving pan-cancer clinical validation[41]. The incidence and mortality of CRC remains high among solid tumors, making it a major threat to human health[1]. Currently, Food and Drug Administration-approved drugs for CRC primarily include immunotherapy drugs and agents targeting specific gene mutations such as KRAS (Table 2).SHP2 functions as a pivotal signaling hub within the CRC signaling network, exerting pleiotropic effects on multiple oncogenic pathways. This unique characteristic provides novel opportunities for precision oncology and unlocks innovative avenues to overcome resistance to conventional therapies[20,22,23,29]. However, despite their therapeutic potential, SHP2 inhibitors carry some challenges such as off-target effects and pharmacokinetic limitations, which collectively limit their therapeutic efficacy in patients[44,45]. SHP2-targeted therapies in CRC demonstrate a "double-edged sword" effect, with therapeutic efficacy highly dependent on specific mutational subtypes. Combination strategies (e.g., immunotherapy) and precision stratification are critical for future breakthroughs[40,46]. Currently, multiple clinical trials are underway, with results eagerly anticipated. Overall, SHP2-targeted therapies could emerge as a cornerstone of multimodal CRC treatment frameworks, providing synergistic effects with existing therapies to address tumor heterogeneity and adaptive resistance.

Table 2 Food and Drug Administration-approved drugs for colorectal cancer.

Drug name	Target	Approval year	Current clinical use	Developer/company
Cetuximab	HER1 (EGFR/ErbB1)	2004	First-line therapy for KRAS wild-type CRC combined with chemotherapy	Bristol-Myers Squibb
Panitumumab	HER1 (EGFR/ErbB1)	2006	Preferred in EU/US	Takeda/Amgen
Regorafenib	KIT/PDGFRβ/RAF/RET	2012	Third-line therapy for refractory CRC, OS extended by 2.5 months	Bayer
Aflibercept	VEGFA/B	2012	Combined with FOLFIRI for second-line therapy in EU/US	Sanofi
Ramucirumab	VEGFR2	2014	Primarily used in gastric cancer; limited CRC application	Eli Lilly
Bevacizumab	VEGFR	2004	Cornerstone agent combined with chemotherapy across lines	Genentech
Encorafenib	BRAFV600E	2020	Core drug in triple therapy for BRAF-mutant CRC	Bristol-Myers Squibb
Pembrolizumab	PD-1	2017	First-line immunotherapy for MSI-H/dMMR CRC	Merck & Co.
Ipilimumab	CTLA-4	2011	Combined with PD-1 inhibitors for MSI-H CRC	Bristol-Myers Squibb
Fruquintinib (FRUZAQLA)	VEGFR1/2/3	2023	Previously treated metastatic CRC, regardless of biomarker status	Takeda/HUTCHMED
Trifluridine/tipiracil+bevacizumab	Thymidine analog + TP inhibitor + VEGF	2023	Metastatic CRC progressing after prior chemotherapy and anti-VEGF/EGFR therapies	Taiho Oncology
Encorafenib+cetuximab+mFOLFOX6	BRAFV600E + EGFR	2024	Metastatic CRC with BRAFV600E mutation (accelerated approval)	Pfizer/Array BioPharma
Sotorasib + panitumumab	KRASG12C + EGFR	2025	KRASG12C-mutated metastatic CRC	Amgen
Nivolumab	PD-1	2024	MSI-H/dMMR metastatic CRC progressing after fluoropyrimidine, oxaliplatin, and irinotecan	Bristol Myers Squibb
Nivolumab+ipilimumab	PD-1 + CTLA-4	2025	First-line treatment for unresectable or metastatic MSI-H/dMMR CRC	Bristol Myers Squibb

CRC: Colorectal cancer; OS: Overall survival; MSI-H: Microsatellite instability high; dMMR: DNA mismatch repair deficiency.