SHP2 Inhibitors Open the Door to Treat KRAS-Mutant Cancers

Ravi Salgia, MD, PhD

Could SHP2, which plays a role in both tumor and immune cell signaling, be the next target of effective treatments for patients whose cancer does not respond to traditional therapies or relapses?¹ SHP2 (SRC homology region 2–containing protein tyrosine phosphatase 2), encoded by the PTPN11 gene, is generating continued interest in oncology research. Agents that inhibit SHP2 attack cancer cells in a way that is distinct from other therapies, and data showing the potential efficacy of such therapies, are fueling more research.

The discovery of the first RAS oncogene in 1964 produced great excitement in the cancer research community.² It led to a race to determine the oncogene’s cellular role and how to possibly exploit it for therapeutic purposes. Activating mutations in a RAS homologue, KRAS, are found in almost 20% of patients with cancer, particularly pancreatic, colon, and non–small cell lung cancers. KRAS inhibitors have been demonstrated to be effective in treating such malignancies. Unfortunately, optimizing KRAS inhibitors has proved challenging. Many cancer cells develop adaptive resistance to these agents by increasing expression of upstream receptor tyrosine kinases (RTKs) or their ligands, which makes finding effective treatments even more difficult.³

SHP2, an oncogenic tyrosine phosphatase involved in signal transduction downstream of several RTKs, has been associated with several types of cancer. These include leukemia and breast, gastric, laryngeal, liver, lung, and oral cancers, as well as other diseases.⁴ Acting upstream of RAS, SHP2 is necessary for full activation of the MAPK pathway. If clinicians could suppress SHP2 activity, that would inhibit RAS/MAPK signaling and the tumor cell survival and proliferation that it promotes.

SHP2 has also been considered “undruggable,” a protein that oncologists found impossible to target with drugs5—until now. As a phosphatase, SHP2 represents an unusual therapeutic target.

“SHP2 is an interesting molecule. Primarily what we use now in therapeutics are inhibitors of proteins called kinases, and kinases add modifications to other proteins that drive signaling pathways required for tumor cells to proliferate,” explained Michael K. Wendt, PhD, an associate professor of medicinal chemistry and molecular pharmacology at Purdue Center for Cancer Research in West Lafayette, Indiana, in an interview with Targeted Therapies in Oncology.

“We have been working—myself, as an example—over 30 years in medical oncology, trying to break the code for lung cancer,” said Ravi Salgia, MD, PhD, in an interview with Targeted Therapies in Oncology. Salgia is a professor in the Department of Medical Oncology and Therapeutics Research and Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope, a comprehensive cancer center near Los Angeles, California. “We’ve made huge strides, for example, in [treating cancers with mutations in] EGFR and ALK, and ROS1 and BRAF. But with RAS we were never able to make a big impact.”

Results of recent studies investigating SHP2 may change that. Findings from recent phase 1 trials presented at the American Association for Cancer Research (AACR) Annual Meeting 2021, held April 10 to 15 and May 17 to 21, suggest that some SHP2 inhibitors have the potential to be developed into anticancer agents.

In an article in Scientific Reports in January 2021, investigators from the Novartis Institutes for BioMedical Research reviewed findings from their preclinical SHP2 blockade experiments.1 They found that inhibition of SHP2 enhanced the immune-mediated killing of cancer cells by boosting tumor-intrinsic IFNγ signaling, which, in turn, resulted in “…enhanced chemoattractant cytokine release and cytotoxic T-cell recruitment, as well as increased expression of MHC class I and PD-L1 on the cancer cell surface.”

More SHP2 Research

Investigators in China are developing ETS-001, a highly potent allosteric SHP2 inhibitor that has potential for treating RAS/MAPK–driven cancers.6 They found that using ETS-001 as a single agent dramatically inhibited the growth of cancer cells, both in vitro and in vivo tumor models with mutations in EGFR or in components of the nucleotide cycling–dependent KRAS pathway. “Besides, as the effectiveness of RAS pathway inhibitors [is] ultimately limited by rapid emergence of drug resistance via multiple mechanisms, including bypass activation of alternative RTKs, SHP2 inhibition has the potential to overcome the resistance as [part of] combinational strategies associated with various RAS pathway–targeted therapies,” the authors wrote. “We show that ETS-001 exhibited strong synergistic effect with EGFR-tyrosine kinase inhibitors (osimertinib [Tagrisso]), KRAS G12Ci [AMG510], or CDK4/6i (ribociclib [Kisqali]) in appropriate cancer models in vitro and in vivo.”

The investigators concluded that their findings provided preclinical evidence that ETS001 may effectively treat RAS/MAPK–altered tumors either alone or in combination with other targeted therapies.⁶

According to a second presentation at the conference, RMC-4630 is a potent, selective, orally bioavailable allosteric SHP2 inhibitor.^7,8 The investigators noted that preclinically, inhibition of SHP2 reduced tumor growth not only by suppressing RAS signaling but also by transforming the tumor immune microenvironment.

“SHP2 actually acts in the opposite fashion of kinases. Kinases add phosphate groups to proteins, but the P part of the SHP2 acronym stands for phosphatase. These molecules remove phosphate groups from proteins,” Wendt said. “And interestingly, however, SHP2 is still somehow required for these proliferation pathways to take place. [The reason for this is] not completely understood.”

Determining the kind of signal can be hard, as can identifying which toxicities may occur with a novel SHP2 inhibitor, said Salgia. “You need to do phase 2 studies, phase 3 studies, to be able to say if it is going to play an important role in our therapeutic armamentarium… especially [in patients] with KRAS [mutations].” He pointed out that investigators must also evaluate whether a new agent would be used as monotherapy or as part of a combination, as well as how to approach the development of resistance.

Targeting Specific Cancers

Any cancer with a KRAS mutation has the potential for treatment with SHP2 inhibition; this has created buzz among investigators. “We know, for example, colon cancer has KRAS mutations,” Salgia explained. “We know that pancreatic cancer has KRAS mutations. Other cancers do as well. But not all mutations are created equal, and not all cancers are created equal,” he cautioned. For example, both small cell lung cancer and colon cancer can be treated with topoisomerase inhibitors, but they have different levels of sensitivity to specific agents. Both irinotecan and topotecan can be efective in treating small cell lung cancer, but only irinotecan is effective in treating colon cancer.

Caution Needed

Some concern also exists about potential problems with SHP2 inhibition. According to a review published earlier this year, there is evidence that the SHP2 gene and PTEN gene synergistically inhibit liver tumor formation in mice. Therefore, to treat solid tumors such as liver cancer, SHP2 inhibitors should be used with caution as they could also activate STAT3, an important cancer- promoting factor. “Thus, the phosphorylation level of STAT3 should be paid close attention to when trying to treat related solid tumors with SHP2 inhibitors,” the authors wrote.

Early Days Yet

SHP2 inhibitors hold tremendous potential; however, whether this potential will be realized remains to be seen, particularly given that the cellular function of SHP2 is very different from that of most cancer therapy targets.

“SHP2 is a phosphatase, and an inhibitor of a phosphatase has never made it this far [in targeted cancer therapy development],” Wendt said. “It’s new ground in terms of the effects we’re seeing, and preclinical experiments are just the tip of the iceberg. [The efficacy of these agents] could actually get better in clinical experiments. Another exciting thing around SHP2 is there are studies coming out now showing that in addition to [reducing] cancer cell proliferation, SHP2 inhibition can also aid in the ability of the immune system to sense cancer cells and eliminate them.”¹⁰

One of the biggest drawbacks, according to Wendt, is that it is not yet known how to identify which patients would have the best response to this new type of therapy. “I think over the next couple of years, if SHP2 inhibitors continue to develop clinically, a crucial aspect is what do we [test in] patient biopsies to identify [who] might best respond to an SHP2 inhibitor?”

The Takeaway

Several clinical trials are planned for the future. Phase 1 and 2a trials are currently recruiting patients with advanced solid tumors to test potential treatments (TABLE).

Although there is always hope that the trial will provide an effective treatment for the participant, patients often enroll in trials to help research progress, which in turn may help others with cancer years later. If community oncologists encourage their patients to participate in clinical trials, the patients become involved in the process.

Salgia said that oncologists are always optimistic about their patients’ future, although SHP2-directed treatments are still a long way from being commercially available. “What I tell our patients is, you have this current therapy and our goal is to get you to the next level. And suppose you have a recurrence or resistance, then by that time, we may have more therapies available.”

_References:

_{1. Wang Y, Mohseni M, Grauel A, et al. SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms. Sci Rep. 2021;11(1):1399. doi:10.1038/s41598-021-80999-x}

_{2. Weiss RA. A perspective on the early days of RAS research. Cancer Metastasis Rev. 2020;39(4):1023-1028. doi:10.1007/s10555-020-09919-1}

_{3. Mukhopadhyay S, Fedele C, Neel BG. SHP(ing) out oncogenic KRAS towards therapeutics. National Cancer Institute. April 15, 2021. Accessed April 30, 2021. https://www.cancer.gov/research/key-initiatives/ras/ ras-central/blog/2021/neel-shp2-inhibitors}

_{4. Zhang J, Zhang F, Niu R. Functions of Shp2 in cancer. J Cell Mol Med. 2015;19(9):2075-2083. doi:10.1111/jcmm.12618}

_{5. Song Z, Wang M, Ge Y, et al. Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies. Acta Pharm Sin B. 2021;11(1):13-29. doi: 10.1016/j.apsb.2020.07.010}

_{6. Xia X, Du L, Zhuge H, et al. Discovery of ETS-001, a highly potent allosteric SHP2 inhibitor to treat RTK/RAS-driven cancers. Presented at: AACR Annual Meeting 2021; April 10-15 and May 17-21, 2021; Virtual. Accessed May 14, 2021. https://bit.ly/3vbw1bJ}

_{7. Nichols RJ, Haderk F, Stahlhut C, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol. 2018;20(9):1064-1073. doi:10.1038/s41556-0180169-1}

_{8. Quintana E, Schulze CJ, Myers DR, et al. Allosteric inhibition of SHP2 stimulates antitumor immunity by transforming the immunosuppressive environment. Cancer Res. 2020;80(13):2889-2902. doi:10.1158/00085472.CAN-19-3038}

_{9. Luo X, Liao R, Hanley KL, et al. Dual Shp2 and Pten deficiencies promote non-alcoholic steatohepatitis and genesis of liver tumor-initiating cells. Cell Rep. 2016;17(11):2979-2993. doi:10.1016/j.celrep.2016.11.048}

_{10. Chen AY, Haura E, Pacheco J, et al. Modulation of innate and adaptive immunity in blood and tumor of patients receiving the SHP2 inhibitor RMC4630. Presented at: AACR Annual Meeting 2021; April 10-15 and May 1721, 2021; Virtual. Accessed May 10, 2021. https://bit.ly/3u8r4iO}