Reference Detail

Ref Type

Journal Article

PMID

(38992135)

Authors

Whitehead CE, Ziemke EK, Frankowski-McGregor CL, Mumby RA, Chung J, Li J, Osher N, Coker O, Baladandayuthapani V, Kopetz S, Sebolt-Leopold JS

Title

A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature cancer	5	8	2024 Aug	1250-1266	Nat Cancer

URL

Abstract Text

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
MTX-531	MTX-531	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
MTX-531		MTX531\|MTX 531	EGFR Inhibitor (Pan) 62 PI3K Inhibitor (Pan) 42	MTX-531 inhibits EGFR and PI3K, which results in decreased Egfr and Pi3k signaling and potentially leads to increased apoptosis and decreased tumor growth (PMID: 38992135).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	colorectal cancer	sensitive	MTX-531 + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, treatment with the combination of Mekinist (trametinib) and MTX-531 inhibited tumor growth with a 40% partial response rate and increased survival in a patient-derived xenograft (PDX) model of colorectal cancer harboring BRAF V600E (PMID: 38992135).	38992135