Intratumoral Cellular Heterogeneity: Implications for Drug Resistance in Patients with Non-Small Cell Lung Cancer

SIMPLE SUMMARY: The number of druggable tumor-specific molecular alterations in the treatment of non-small cell lung cancer (NSCLC) has grown significantly in the past decade. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers and develop personalized treatments. However, although new therapies confer prolonged disease control and high tumor response rates, most patients eventually progress on targeted treatments. Intratumoral heterogeneity is a frequent event in NSCLC, driving the tumor cells to develop adaptive or new resistance mechanisms within the drug environment. This review summarizes the current and upcoming research on the biological role of tumor heterogeneity, highlighting the link between early and acquired drug resistance and tumoral heterogeneity in targetable driver mutated NSCLC. ABSTRACT: Tailored therapies based on the identification of molecular targets currently represent a well-established therapeutic scenario in the treatment of non-small cell lung cancer (NSCLC) patients. However, while aiming to improve patients’ response to therapy, development of resistance is frequently observed in daily clinical practice. Intratumoral heterogeneity is a frequent event in NSCLC, responsible for several critical issues in patients’ diagnosis and treatment. Advances in single-cell sequencing technologies have allowed in-depth profiling of tumors and attributed intratumoral heterogeneity to genetic, epigenetic, and protein modification driven diversities within cancer cell populations. This review highlights current research on the biological role of tumor heterogeneity and its impact on the development of acquired resistance in NSCLC patients.