Ines Pulido

Equity in precision cancer health, defined here as equitable access to inclusive cancer risk assessment, cancer risk reduction/management, and risk-appropriate cancer healthcare from prevention through survivorship, is critical for addressing broader population cancer disparities. Specifically, we describe the impact of the Illinois Cancer Health Equity Research (I-CHER) Center on precision cancer health equity, including how the Center cumulatively served >10,000 residents from under-resourced communities; disseminated findings to >300 members of the local cancer health disparities workforce; and translated scientific solutions into sustained clinical practice and two state laws. The objective of this case report is to describe the I-CHER Center’s multisectoral structure; participatory administrative processes for research; early implementation challenges and tensions across sectors; and solutions that contributed to early center-wide successes. This case report offers one example of the administrative infrastructure needed for advancing scientific solutions in precision cancer health equity within a Minority Serving Institution (MSI) and its internal federally qualified health center (FQHC).

Supplementary Figure S3 shows that dual inhibitors simultaneously target KRAS G12D and HSP90. Specifically, it demonstrates (A) that DI-1 markedly reduces pERK, pAKT, and total AKT levels in G12D-mutated cell lines; (B) that DI-1 decreases GTP-bound active KRAS and total RAS levels; and (C) that DI-1 more effectively inhibits PANC-1 cell proliferation compared to MRTX1133, onalespib, or their combination.

Supplementary Materials and Methods

Supplementary Figure S4 shows the in vivo efficacy of dual inhibitors against KRAS G12D–mutated models. Specifically, it demonstrates (A) that DI-2 treatment reduces cell viability in G12D-mutated PDOs compared to MRTX1133, as shown by live/dead staining, and (B) that DI-2 broadly suppresses receptor tyrosine kinase (RTK) activation in MRTX1133-resistant PANC-1 cells relative to vehicle, MRTX1133, or PROTAC treatment.

Supplementary Figure S1 shows differential sensitivity to MRTX1133 in G12D-mutated cell lines and patient-derived organoids (PDOs). Specifically, it demonstrates (A–B) that MRTX1133 inhibits pERK, which subsequently reactivates at different times across cell lines and PDOs; (C) that KRAS knockdown decreases pERK only in PANC-1 cells but induces apoptosis in AsPC-1 and SK-LU-1 cells; and (D) that KRAS degradation by a G12D-targeted PROTAC does not reduce pERK or pAKT levels, consistent with cell viability results.

KRASG12D is a common oncogenic driver mutation in diverse cancers, including non–small cell lung cancer, colorectal cancer, and pancreatic cancer. KRASG12D inhibitors have recently progressed into clinical trials but will likely face innate or acquired drug resistance similar to that which has been observed for KRASG12C inhibitors, such as activation of receptor tyrosine kinases, KRAS independence, and reactivation of RAS–MAPK signaling. This study investigates heterobifunctional small-molecule dual inhibitors that simultaneously target both KRASG12D and protein chaperone HSP90 in KRASG12D-mutated cancer cell lines and patient-derived organoids. Our findings reveal that the efficacy of the clinical-stage KRASG12D inhibitor MRTX1133 varies, with notable resistance being observed in some cell line and organoid models. In contrast, KRASG12D–HSP90 dual inhibitors were found to broadly display superior effectiveness in inducing apoptosis, reducing cell viability, and suppressing key downstream signaling pathways such as AKT and ERK1/2 in MRTX1133-resistant models. The rationale for targeting HSP90, which is preferentially activated in cancer cells, alongside KRASG12D, arises from the ability of HSP90 inhibition to destabilize substrate client proteins that are essential for cancer cell survival and have also been implicated in resistance to KRAS inhibitors. This dual-inhibitor approach presents a promising new strategy to combat de novo and acquired drug resistance in KRASG12D-mutated cancers and potentially paves the way for improved clinical outcomes by addressing the complex molecular mechanisms underlying cancer cell evolution that enables resistance to conventional inhibitors.

Supplementary Figure S2 shows that MRTX1133 treatment activates receptor tyrosine kinases (RTKs) to overcome KRAS G12D inhibition. Specifically, it demonstrates (A) increased phosphorylation and activation of EGFR family members and other RTKs in a model-dependent manner after 72 hours of MRTX1133 treatment, and (B) unchanged KRAS, HRAS, and NRAS mRNA levels in treated G12D-mutated PDOs.

Compound Synthesis Information

KRAS G12D is a common oncogenic driver mutation in diverse cancers, including non–small cell lung cancer, colorectal cancer, and pancreatic cancer. KRASG12D inhibitors have recently progressed into clinical trials but will likely face innate or acquired drug resistance similar to that which has been observed for KRASG12C inhibitors, such as activation of receptor tyrosine kinases, KRAS independence, and reactivation of RAS–MAPK signaling. This study investigates heterobifunctional small-molecule dual inhibitors that simultaneously target both KRASG12D and protein chaperone HSP90 in KRASG12D-mutated cancer cell lines and patient-derived organoids. Our findings reveal that the efficacy of the clinical-stage KRASG12D inhibitor MRTX1133 varies, with notable resistance being observed in some cell line and organoid models. In contrast, KRASG12D–HSP90 dual inhibitors were found to broadly display superior effectiveness in inducing apoptosis, reducing cell viability, and suppressing key downstream signaling pathways such as AKT and ERK1/2 in MRTX1133-resistant models. The rationale for targeting HSP90, which is preferentially activated in cancer cells, alongside KRASG12D, arises from the ability of HSP90 inhibition to destabilize substrate client proteins that are essential for cancer cell survival and have also been implicated in resistance to KRAS inhibitors. This dual-inhibitor approach presents a promising new strategy to combat de novo and acquired drug resistance in KRASG12D-mutated cancers and potentially paves the way for improved clinical outcomes by addressing the complex molecular mechanisms underlying cancer cell evolution that enables resistance to conventional inhibitors.