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Response and resistance to SHP2 inhibitors alone and in combination in Non-Small Cell Lung Cancer

Award Number: R01CA248896
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/10/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Response and resistance to SHP2 inhibitors alone and in combination in Non-Small Cell Lung Cancer - Despite recent advances in targeted and immune-therapies, there is an urgent need for new therapeutic approaches for metastatic non-small cell lung cancer (NSCLC). SH2 domain-containing phosphatase-2 (SHP2), encoded by PTPN11, is a key “positive” signaling component, required for RAS/ERK MAP kinase activation by receptor tyrosine kinases (RTKs) and cytokine receptors, as well as by oncogenic amplified RTKs and protein-tyrosine kinase (PTK) fusion proteins. Recently, potent, orally available, highly specific SHP2 inhibitors were developed. These agents inhibit amplified RTK/PTK-fusion-driven cells/tumors and are in Phase I clinical trials. Our results suggest that SHP2-inhibitors (SHP2-Is) could have a much broader role in cancer therapy. SHP2-Is block adaptive resistance to MEK inhibitors (MEK-Is) in KRAS-mutant and -WT cells, acting upstream of guanine nucleotide exchange factors (SOS1/2). Consequently, SHP2-Is have single agent efficacy against “cycling” KRAS mutants (e.g., KRASG12C), which retain intrinsic GTPase activity. Supported by extensive Preliminary Data, we hypothesize that SHP2-Is will also enhance the efficacy of newly developed KRASG12C (G12C) inhibitors in G12C-mutant NSCLC, the effects of MEK-Is in Osimertinib (Osi)-resistant EGFR- mutant NSCLC, and the effects of Osi in Osi-sensitive EGFR-mutant NSCLC. SHP2 also binds immune checkpoint receptors, including PD1, might inhibit immune receptor signaling, and has complex effects on myeloid cells and other cells in the tumor microenvironment (TME). These pleiotropic actions position SHP2 at the nexus of targeted and immune therapies. This MPI application joins experts in SHP2 action (NEEL) and NSCLC translational biology (WONG) to clarify the utility of SHP2-Is as NSCLC therapeutics. We will: (1) test combinations of SHP2-Is with covalent RASG12C inhibitors, MEK-Is, and EGFR-inhibitors in KRAS- and EGFR-mutant NSCLC GEMMs; (2) clarify cell-autonomous and non-autonomous effects of these combinations using state-of-the art immune assays, drug-resistant tumor cells, immune cell depletion and new, inducible SHP2-I-resistant GEMMs; and (3) analyze recurrent tumors and perform CRISPR/Cas9 screens to identify the landscape of resistance to these agents.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $702,059 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	001	5	6/12/2025	NON-COMPETING CONTINUATION	$70,206
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	5	11/4/2024	NON-COMPETING CONTINUATION	$631,853
														Subtotal = $702,059

Issue Date FY: 2024 ( Subtotal = $666,956 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	4	11/30/2023	NON-COMPETING CONTINUATION	$631,853
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$35,103
														Subtotal = $666,956

Issue Date FY: 2023 ( Subtotal = $688,018 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	001	3	3/15/2023	NON-COMPETING CONTINUATION	$56,165
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	3	11/15/2022	NON-COMPETING CONTINUATION	$631,853
														Subtotal = $688,018

Issue Date FY: 2022 ( Subtotal = $688,018 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	2	11/24/2021	NON-COMPETING CONTINUATION	$631,852
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	001	2	5/13/2022	NON-COMPETING CONTINUATION	$56,166
														Subtotal = $688,018

Issue Date FY: 2021 ( Subtotal = $703,176 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	1	12/9/2020	NEW	$703,176
														Subtotal = $703,176

Grand Total All Awards = $3,448,227

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Response and resistance to SHP2 inhibitors alone and in combination in Non-Small Cell Lung Cancer

Award Number: R01CA248896

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/10/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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