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Investigating oncogenic mutations and regulatory mechanisms of HER2 by electron microscopy

Award Number: F30CA247147
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/11/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Investigating oncogenic mutations and regulatory mechanisms of HER2 by electron microscopy - PROJECT SUMMARY/ABSTRACT The goal of this proposal is to address fundamental gaps in our understanding of HER2 receptor tyrosine kinase (RTK) activation mechanism and regulation through direct structural and biophysical studies on nearly full-length receptor. Aberrant HER2 signaling through amplification or oncogenic mutations is at the root of many cancers and remains a key target of therapies. HER2, together with EGFR, HER3, and HER4 comprise the Human Epidermal Growth Factor Receptor (HER) family of RTKs, indispensable for cellular homeostasis. These receptors convert extracellular cues into intracellular responses through homo- and hetero- oligomerization induced by growth factor binding. HER2 distinguishes itself as an orphan receptor with no known ligand and signals by heterodimerization with other members of the HER family. We do not understand how HER2 regulates its catalytic activity in the absence of ligand-bound co-receptors, but many HER2 oncogenic mutations compromise these mechanisms and confer activity in a co-receptor independent manner. Several of those mutations fall outside of the kinase domain, but in the absence of structural understanding of how growth factor binding on the extracellular side of the receptor increases the catalytic activity of the receptor’s intracellular kinase domain, we cannot predict how these mutations elevate HER2 signaling, and most importantly change HER2 vulnerability to known therapeutics. We hypothesize that the orphan receptor HER2 features intrinsic structural mechanisms to regulate catalytic activity in the absence of ligand or co- receptor and oncogenic mutations outside of the kinase domain overcome these regulatory mechanisms via alterations in oligomerization or conformational states to produce aberrant activation. Addressing our hypotheses relies on biophysical analyses of the receptor as a whole. In Aim 1 we seek to determine a high-resolution structure of near-full length HER2 by cryo-electron microscopy (cryo-EM). The lack of any high-resolution structure of a full-length RTK is attributed to challenges in expressing, purifying, and stabilizing a homogeneous receptor sample. We have recently overcome these challenges for HER2 by engineering a near-full length HER2 construct that is robustly expressed and purified in a stable form. Our preliminary negative stain-electron microscopy imaging demonstrates high sample homogeneity that permits structural investigations by cryo-EM. In Aim 2, we will leverage our abilities in isolating HER2 to biophysically characterize the influence of HER2 oncogenic mutations on oligomerization state and structure by EM. We will then correlate the in vitro observations with downstream signaling. The completion of this multidisciplinary project will represent a significant scientific contribution, not only due to the technological advances required to study single-pass transmembrane receptors but also in the light of learning how HER2 regulates itself without ligand or co-receptor. Such knowledge could be applied to developing new drugs, selectively targeting mutant forms of HER2, and counteracting drug resistance common with anti-HER2 therapies.


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: 2024 ( Subtotal = -$16,547 )
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Research Manpower	001	4	6/24/2024	NON-COMPETING CONTINUATION	$0
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Research Manpower	000	4	5/20/2024	NON-COMPETING CONTINUATION	-$16,547
														Subtotal = -$16,547

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	001	4	5/22/2023	NON-COMPETING CONTINUATION	$942
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	000	4	11/3/2022	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	001	3	5/27/2022	NON-COMPETING CONTINUATION	$716
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	000	3	12/8/2021	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $37,799 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	000	2	11/5/2020	NON-COMPETING CONTINUATION	$37,283
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	001	2	2/3/2021	NON-COMPETING CONTINUATION	$516
														Subtotal = $37,799

Issue Date FY: 2020 ( Subtotal = $37,283 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	001	1	12/10/2019	NEW	$0
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	000	1	12/10/2019	NEW	$36,779
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	002	1	2/11/2020	NEW	$504
														Subtotal = $37,283

Grand Total All Awards = $162,981

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Investigating oncogenic mutations and regulatory mechanisms of HER2 by electron microscopy

Award Number: F30CA247147

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/11/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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