Skip to content

SHP2 Inhibitors: Progress and Perspectives in 2024

decorative image with article title "SHP2 Inhibitors: Progress and Perspectives in 2024

In 2024, SHP2 inhibitors (SHP2i) remain at the forefront of drug discovery, particularly in the realm of oncology.  While there are some perspectives suggesting that the emphasis on SHP2 may indicate a disproportionate preference for well-established targets, current developments underscore their continuing significance. This article integrates recent advancements, preclinical discoveries, and results from recent clinical trials to present a brief, yet comprehensive overview of the role of SHP2i in current and future therapeutic strategies.

Overview of Clinical Advances and Combination Therapies

SHP2 (Src homology region 2-containing protein tyrosine phosphatase-2) is implicated in multiple oncogenic pathways, most notably the RAS/MAPK pathway. Its involvement in cancer cell proliferation and survival mechanisms underscores its value as a therapeutic target.

The latest studies, such as those led by Johns Hopkins Kimmel Cancer Center, demonstrate the effectiveness of SHP2 inhibitors in combination with other drugs for treating conditions like malignant peripheral nerve sheath tumors (MPNSTs), which have historically been challenging to manage with conventional treatments [1].

Researchers at Pfizer recently published data which leveraged the early introduction of combination therapy in a phase I trial, which established a proof-of-concept combination therapy with a novel SHP2i for overcoming bypass-signaling-mediated resistance in a clinical setting in which neither monotherapy component was active on its own [2]. Further progress has been made by Jacobio, who recently announced the Center for Drug Evaluation (CDE) approval of a registrational phase III clinical trial of the combination therapy between its novel KRAS G12C inhibitor glecirasib and novel SHP2i (JAB-3312) in China [3]. If the trial moves forward, JAB-3312 will be the first SHP2 inhibitor entered into a phase III study globally in combination with a KRAS G12C inhibitor.

Additionally, a recent review published in Cancer Cell further highlighted the promise of SHP2 inhibitors as a relatively universal approach to adaptive drug resistance, when used in vertical, upstream pathway inhibition with KRAS-G12C inhibitors. Furthermore, SHP2 inhibitors have demonstrated beneficial impact on cells in the tumor microenvironment (TME), so their potential to exert a dual mechanism of action in cancer therapy makes them a promising therapeutic option, especially in combination with other treatments [4].

According to Alessandro Carugo, PhD, Head of Oncology at IRBM, “Dual targets in oncology – specifically those with both antitumor effects and immunomodulation – might represent a unicorn approach to treatment. While there are, of course, other examples, the true potential of combination therapy with SHP2 inhibitors, and the best way to introduce them into clinical practice, has still not been completely elucidated.”

 

Image of a cancer cell and various pathways and blockades targeting tumor growthFigure 1. Image courtesy of Cancer Cell 2024 42338-357DOI: (10.1016/j.ccell.2024.02.012). Potential immunotherapy approaches targeting KRAS mutant tumors as single therapies or in combination with KRAS inhibitors, with red squares showing therapies that inhibit immune suppression mechanisms. Green squares indicate therapeutic strategies that activate immune targeting of KRAS mutant tumors. KRAS*: activated mutant KRAS. Image created with BioRender.com

 

Smart and Preclinical-Informed Combinations

Recent advances in understanding of the RAS-MAPK signaling pathway have positioned SHP2 as a crucial therapeutic target, with its allosteric inhibition emerging as a strategic node to disrupt oncogenic signaling pathways. For example, like Jacobio’s SHP2i, the combination of KRAS G12C inhibitors with Novartis’s SHP2i (TNO155), has shown promising preliminary results in non-small cell lung cancer (NSCLC), highlighting the potential to overcome resistance mechanisms and enhance therapeutic efficacy [5].

These advancements, underpinned by a deep molecular understanding of cancer biology, emphasize the importance of informed combination strategies. Significantly, the integration of biomarker-driven patient selection into the development of these combination therapies heralds a new era in precision oncology. This approach aims to exploit vulnerabilities in the cancer signaling network for improved patient outcomes, leveraging robust preclinical data to tailor treatments to the unique genetic landscape of each tumor.

Novel and Less Explored Indications

In the evolving landscape of cancer therapy, the discovery of a brain permeable SHP2i (I-1000233) by scientists at IRBM marks a significant step forward, particularly for novel and less explored indications such as CNS tumors and metastases.

By leveraging the advantages of allosteric modulation, the novel SHP2i achieves high selectivity and potency against SHP2, crucial for transducing signals in the RAS-MAPK pathway involved in tumor growth and survival. Its unique property of crossing the blood-brain barrier opens new avenues for treating CNS malignancies, a domain where therapeutic options are markedly limited.

Furthermore, its ability to overcome resistance to EGFR inhibitors positions I-1000233 as a versatile tool in combating various forms of cancer, including those that have eluded current therapeutic strategies. The compound’s promising preclinical efficacy and favorable pharmacokinetic profile underscore its potential to meet an unmet medical need for patients with RAS-driven cancers, particularly those affecting the brain.

Overcoming Skepticism with Innovation

While some industry observers might question the continued focus on SHP2 inhibitors, labeling them as less novel, the tangible progress in clinical outcomes and the strategic importance of SHP2 in combination therapies speak to their enduring relevance. The skepticism often stems from a broader discussion about the pace of innovation in drug discovery and the challenge of finding truly novel targets. However, the evolving understanding of SHP2’s role in cancer biology and its potential in overcoming drug resistance mechanisms reinforces its status as a critical target for ongoing and future research.

Moving Forward

As we look ahead, the role of SHP2 inhibitors in cancer therapy appears increasingly significant, bolstered by clinical trials, combination therapy strategies, and innovative discovery platforms. The ongoing research and development efforts not only address the current limitations of cancer treatment but also open up new possibilities for targeting other diseases where SHP2 plays a crucial role.

Despite the discourse around the novelty of research targets, the advancements in SHP2 inhibitor research in 2024 illustrate a promising field characterized by dynamic innovation and the potential for significant clinical impact. As the drug discovery landscape continues to evolve, SHP2 inhibitors stand as a testament to the complex interplay between scientific curiosity, clinical need, and the relentless pursuit of better therapeutic options.

For professionals and executives in the drug discovery and pharmaceutical industries, the trajectory of SHP2 inhibitor research and development offers valuable insights into the challenges and opportunities inherent in bringing novel cancer treatments from the laboratory to the clinic. The integration of new platforms like Direct-to-Biology with traditional drug development processes promises not only to enhance the efficiency of research but also to deliver more effective and targeted therapies to patients in need.

As scientists continue to explore the potential of SHP2 inhibitors and other targeted therapies, the commitment to innovation, collaboration, and patient-focused research remains crucial; and the challenging journey from discovery to clinical application is a testament to the scientific community’s dedication to advancing healthcare and improving patient outcomes in cancer therapy and beyond.

References

  1. Wang, J. et al. CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors. Science Advances, 9, eadg8876 (2023). DOI: 10.1126/sciadv.adg8876.
  2. Drilon, A. et al. SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy. Cancer Discovery, 13, 1789–1801 (2023).
  3. Molina-Arcas, M., Downward, J. Exploiting the therapeutic implications of KRAS inhibition on tumor immunity. Cancer Cell, 42(3), 338-357 (2024). DOI: 10.1016/j.ccell.2024.02.012.
  4. (2024, February 18). Jacobio Announces China CDE Clearance for Phase III Clinical Trial of SHP2 Inhibitor Plus KRAS G12C Inhibitor. Press Release. https://www.jacobiopharma.com/en/news/Jacobio_Announces_China_CDE_Clearance_for_Phase_III_Clinical_Trial_of_SHP2_Inhibitor_Plus_KRAS_G12C_Inhibitor
  5. Negrão, M.V. et al. MA06.03 KontRASt-01: Preliminary Safety and Efficacy of JDQ443 + TNO155 in Patients with Advanced, KRAS G12C-Mutated Solid Tumors. Journal of Thoracic Oncology, 18, S117-S118 (2023). DOI: 10.1016/j.jtho.2023.09.151.
Back To Top