# Targeting cell state transitions driving resistance to KRAS inhibitors in lung cancer

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $735,635

## Abstract

Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer
mortality. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem
cells by self-renewing and replacing alveolar type 1 (AT1) cells. The first allele-specific KRAS inhibitors (KRASi)
were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. Histologic
transformation of LUAD to squamous cell cancer (adenosquamous transition, AST) has been reported as a form
of acquired resistance to KRASi. Such cancer cell state transitions are emerging as central mechanisms of
resistance to oncologic therapies. Importantly, they are not associated with acquired genetic events but are
driven by epigenetic reprogramming and transcriptional re-wiring of cellular differentiation programs. To meet
the challenge of treatment resistance in the clinic, identifying and targeting cell states that confer resistance to
KRAS inhibitors must be sought with urgency. We used genetically engineered mouse models, patient-derived
xenografts and organoids, and patient samples to identify LUAD differentiation states that drive resistance to
KRASi. We found KRASi promote a quiescent AT1-like cancer cell state in LUAD tumors. The AT1-like LUAD
cells exhibit high growth potential upon treatment cessation, whereas ablation of the AT1-like cells sensitizes
tumors to KRASi and robustly improves treatment response. Notably, targeting KRAS in LUAD tumors harboring
mutations in STK11, encoding the LKB1 tumor suppressor, invariably leads to histologic transformation into AST
that is resistant to KRASi. These findings implicate genetically deterministic differentiation programs as key
drivers of resistance to KRASi in lung cancer, whereby LKB1-proficient cancer cells adopt an AT1-like state and
LKB1-deficient cells undergo a squamous transformation. We hypothesize targeting either the AT1-like or the
squamous transition state, informed by LKB1status, will overcome resistance to KRASi in LUAD. To address
this hypothesis, we will (i) investigate the origin and fate of the alveolar/squamous states in tumors using lineage-
tracing; (ii) model outcomes of cytoablative therapies targeting the AT1-like/squamous states utilizing lineage-
ablation; (iii) uncover molecular cell state drivers and evaluate them as targets in the context of LKB1 proficiency
or deficiency. To do this, we will take advantage of novel genetically engineered mouse models (GEMMs) of
KRAS(G12D) or KRAS(G12C) mutant LUAD that we have developed. We validate our findings in human patient-
derived tissues and xenografts. Our proposed study will allow us to establish the AT1-like and squamous
transition states (i) as LKB1 genotype-specific biomarkers of intrinsic resistance and relapse potential in LUAD
and (ii) as targets for cytoablative therapies to overcome resistance to KRASi, as well as to identify molecular
drivers of these cell states. Thu...

## Key facts

- **NIH application ID:** 10945054
- **Project number:** 1R01CA293718-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Tuomas Tammela
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $735,635
- **Award type:** 1
- **Project period:** 2024-06-07 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945054

## Citation

> US National Institutes of Health, RePORTER application 10945054, Targeting cell state transitions driving resistance to KRAS inhibitors in lung cancer (1R01CA293718-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10945054. Licensed CC0.

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