SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

Drilon, Alexander; Sharma, Manish; Johnson, Melissa L.; Yap, Timothy A.; Gadgeel, Shirish M.; Nepert, Dale; Feng, Gang; Reddy, Micaela B.; Harney, Allison S.; Elsayed, Mohamed; Cook, Adam W.; Wong, Christina E.; Hinklin, Ronald J.; Jiang, Yutong; Brown, Eric N.; Neitzel, Nickolas A.; Laird, Ellen R.; Wu, Wen-I; Singh, Anurag; Peng, Wei; Ching, Keith A.; Gaudino, John J.; Lee, Patrice A.; Hartley, Dylan P.; Rothenberg, S. Michael

doi:10.1158/2159-8290.cd-23-0361

Cited by 34 publications

(13 citation statements)

References 27 publications

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“…Here, we also show that SHP2 inhibitors can be effectively combined with ALK inhibitors in targeting ALK -mutated neuroblastoma, including those with acquired resistance to ALK-TKI therapies. Interestingly, it has been recently reported that SHP2 inhibition can sensitize oncogene-addicted tumors to retreatment with targeted therapies, including ALK inhibitors, for ALK fusion–positive lung cancer; these effects were observed in preclinical models and patients ( 65 ). In summary, our results suggest that SHP2 combination regimens are a promising therapeutic strategy to further investigate as a possible regimen for patients with neuroblastoma and other solid tumors with multiple genetic aberrations in the RAS/MAPK/SHP2 pathways, to provide opportunities to enhance drug sensitivity and potentially impact resistance to single agents.…”

Section: Discussionmentioning

confidence: 99%

SHP2 Inhibition with TNO155 Increases Efficacy and Overcomes Resistance of ALK Inhibitors in Neuroblastoma

Valencia-Sama,

Kee,

Christopher

et al. 2023

Cancer Research Communications

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Survival rates among patients with high-risk neuroblastoma remain low and novel therapies for recurrent neuroblastomas are required. ALK is commonly mutated in primary and relapsed neuroblastoma tumors and ALK tyrosine kinase inhibitors (TKI) are promising treatments for ALK-driven neuroblastoma; however, innate or adaptive resistance to single-agent ALK-TKIs remain a clinical challenge. Recently, SHP2 inhibitors have been shown to overcome ALK-TKI resistance in lung tumors harboring ALK rearrangements. Here, we have assessed the efficacy of the SHP2 inhibitor TNO155 alone and in combination with the ALK-TKIs crizotinib, ceritinib, or lorlatinib for the treatment of ALK-driven neuroblastoma using in vitro and in vivo models. In comparison to wild-type, ALK-mutant neuroblastoma cell lines were more sensitive to SHP2 inhibition with TNO155. Moreover, treatment with TNO155 and ALK-TKIs synergistically reduced cell growth and promoted inactivation of ALK and MAPK signaling in ALK-mutant neuroblastoma cells. ALK-mutant cells engrafted into larval zebrafish and treated with single agents or dual SHP2/ALK inhibitors showed reduced growth and invasion. In murine ALK-mutant xenografts, tumor growth was likewise reduced or delayed, and survival was prolonged upon combinatorial treatment of TNO155 and lorlatinib. Finally, we show that lorlatinib-resistant ALK-F1174L neuroblastoma cells harbor additional RAS-MAPK pathway alterations and can be resensitized to lorlatinib when combined with TNO155 in vitro and in vivo. Our results report the first evaluation of TNO155 in neuroblastoma and suggest that combinatorial inhibition of ALK and SHP2 could be a novel approach to treating ALK-driven neuroblastoma, potentially including the increasingly common tumors that have developed resistance to ALK-TKIs. Significance: These findings highlight the translatability between zebrafish and murine models, provide evidence of aberrant RAS-MAPK signaling as an adaptive mechanism of resistance to lorlatinib, and demonstrate the clinical potential for SHP2/ALK inhibitor combinations for the treatment of ALK-mutant neuroblastoma, including those with acquired tolerance or potentially resistance to ALK-TKIs.

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Section: Discussionmentioning

confidence: 99%

SHP2 Inhibition with TNO155 Increases Efficacy and Overcomes Resistance of ALK Inhibitors in Neuroblastoma

Valencia-Sama,

Kee,

Christopher

et al. 2023

Cancer Research Communications

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“…Although the earliest first-in-human studies generally enrolled all tumor genotypes, some of the later studies have taken a more targeted approach by enrolling mutant genotypes thought to be most sensitive to SHP2 inhibition, such as ALK- or ROS1-positive NSCLC, BRAF V600E colorectal cancer, or NF1-mutant or BRAF class 3–mutant solid tumors (e.g., PF-07284892 in NCT04800822; ref. 109 ). Another interesting strategy is the exclusion of known activating mutations in RAS or BRAF, which may render tumors resistant to SHP2 inhibition (e.g., TNO155 in NCT03114319).…”

Section: Clinical Development Of Shp2imentioning

confidence: 99%

SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment

Sodir,

Pathria,

Adamkewicz

et al. 2023

Cancer Discovery

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The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response. Significance: The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.

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“…For example, preclinical data demonstrated that select tumors that have progressed on FDA-approved targeted oncogene inhibitors may be resensitized by adding PF-07284892, an inhibitor of the SHP2 tyrosine phosphatase. While most phase I trials require extensive testing of novel drugs as monotherapy prior to allowing combinations, recognition of the need to expedite combination therapy enabled patients to undergo a lead-in period on the SHP2 monotherapy, followed by the addition of the approved inhibitor at progression ( 26 ).…”

Section: Trial Design Evolutionmentioning

confidence: 99%

Precision Oncology: 2023 in Review

Murciano-Goroff,

Suehnholz,

Drilon

et al. 2023

Cancer Discovery

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Summary: This article presents a review of recent major advances in precision oncology and the future implications of these advances, specifying the iterative progress achieved from the end of 2022 through 2023. We discuss the different classes of precision oncology drugs and associated biomarkers as well as the improvements in clinical trial design that have enabled the efficient testing of these drugs.

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SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

Cited by 34 publications

References 27 publications

SHP2 Inhibition with TNO155 Increases Efficacy and Overcomes Resistance of ALK Inhibitors in Neuroblastoma

SHP2 Inhibition with TNO155 Increases Efficacy and Overcomes Resistance of ALK Inhibitors in Neuroblastoma

SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment

Precision Oncology: 2023 in Review

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